Oxford Textbook of Cancer Biology
Francesco Pezzella (ed.) et al.
https://doi.org/10.1093/med/9780198779452.001.0001
Published: 2019
Online ISBN: 9780191824579
Print ISBN: 9780198779452
CHAPTER
23 Cancer immunology 
Herman Waldmann
Pages 330–343
Abstract
Until recently, the prospects for harnessing immune mechanisms to ght cancer were not
encouraging. The advent of monoclonal antibodies, both as diagnostics and as probes for molecular
function, have been important, while the identi cation of dendritic cells as a major intermediary
between the antigen source and T-cell activation has been crucial. Major advances in molecular biology
and the creation of mutant mice lacking de ned gene products have pinpointed key molecules
in uencing immune function. Finally, many translational e orts in vaccination, autoimmune disease,
and transplantation have enabled identi cation of hitherto undervalued mechanisms that the immune
system uses to regulate itself. A fuller understanding of self-tolerance mechanisms, tumour antigens,
and the tumour microenvironment has catalysed a wide range of novel therapeutic strategies and has
also allowed a re-evaluation of mechanisms underlying the bene ts of past chemotherapies.
Keywords: innate immunity, adaptive immunity, immunological privilege, immunological tolerance, AIRE,
Foxp3, dendritic cells, regulatory T cells, alternatively activated macrophages, stress surveillance
Subject: Radiation Oncology
Series: Oxford Textbooks
Collection: Oxford Medicine Online
Why cancer immunology?
The reader may wonder why cancer immunology should be considered a topic distinct from immunology in
general, or from transplantation immunology from which many fundamental concepts of the immune
system have evolved. In confronting pathogens or transplants the immune system is often rapidly exposed
to large doses of non-self-antigens in the context of molecular adjuvant-creating moieties (so-called
molecular patterns) that elicit multiple cascades of immunity (Matzinger, 1994; Medzhitov and Janeway,
1997). In contrast, it is not easy to imagine how a ‘self’ cell which has recently developed su
cient
mutations to become malignant, can provide adequate adjuvant-creating signals, let alone non-selfantigens, to evoke equivalent destructive immune responses. As the malignancy expands what cues, if any,
can it give the immune system that it should respond?
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
https://doi.org/10.1093/med/9780198779452.003.0023
Published: April 2019
Early conjectures were that growing ‘self’ tumour cells could somehow ‘sneak through’ the various proimmunity checkpoints, so bypassing immune reactivity.
The issue of tumour immunogenicity has been, and continues to be, a dilemma for immunologists. Leaving
aside virally induced tumours, would we not be tolerant of the protein’s tumour expressed in our own
tumours? Even if we were not naturally tolerant of some tumour antigens, would these not be shared with
normal tissues? Presumably then, tumour immunity might also risk autoimmunity?
Although answers to these questions are still incomplete, the explosion in fundamental immunology has,
over the past 25 years or so, provided the groundwork for a better understanding of the relationships
between tumours and the immune system. The advent of monoclonal antibodies, both as diagnostics and as
probes for molecular function, have been important. The identi cation of dendritic cells as a major
1998). Major advances in molecular biology and the creation of mutant mice lacking de ned gene products,
has pinpointed key molecules in uencing immune function. Finally, many translational e orts in
vaccination, autoimmune disease, and transplantation have enabled identi cation of hitherto undervalued
mechanisms that the immune system uses to regulate itself. Historically, these had been poorly studied
because it was easier to quantitate immune responses than the lack of them (i.e. self-tolerance). Moreover,
as self-tolerance was largely seen as a fait accompli from birth, research into mechanisms of self-tolerance
has always been particularly demanding.
Against the backdrop of advances in fundamental immunology, there have been several clues that the
immune system could attack cancers, promoting their rejection as if they were ‘foreign’ transplants. From
all these contributions, the notion that tumours simply sneak through the immune system has changed. We
now accept that some tumours can evoke and/or provide su
ciently adjuvant-like signals which, if
adequately sensed, can promote immune reactivity in the host. With this accepted a new hallmark of cancer
can be de ned as the cross-talk between tumours, their supportive stroma, and the immune system, that
impedes immune reactivity using diverse inhibitory mechanisms acting throughout the evolution of that
tumour (Hanahan and Weinberg, 2011). Such suppressive mechanisms, formerly studied solely in relation to
carcinogenesis, are now becoming increasingly relevant to immunoregulation more generally (Zitvogel et
al., 2013; Belvin and Mellman, 2015). At a practical level, an improved understanding of these mechanisms
has suddenly created a major growth industry in practical e orts to give the immune system the upper
hand. These range from conventional small molecule drugs, antibodies, cytokines, and cellular therapies, as
well as a recognition that what were formerly thought of as chemotherapeutic drugs, are, in retrospect,
agents that can also liberate host antitumour immune function in diverse ways. In short, our concepts of
tumour immunology and our application of them are developing fast, being both informed by, but also
informing, fundamental immunology.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
intermediary between the antigen source and T-cell activation has been crucial (Banchereau and Steinman,
The immune system and protection against pathogens
The vertebrate immune system has evolved to protect against microbial infection while minimizing damage
to self. To achieve this, it uses innate mechanisms mediated by plasma proteins and diverse cells to contain
infection long enough for the adaptive system of antigen-speci c lymphocytes to engage, and to generate
responses, best able to clear the microbe. The innate mechanisms have no speci city for the foreign
antigen, but re ect recognition by preformed receptors of one or more forms of perturbation, including
p. 331
microbially-encoded molecular patterns, so-called
pathogen-associated molecular patterns or PAMPS
(Medzhitov and Janeway, 1997; Beutler and Rehli, 2002), comprising proteins, lipids, carbohydrates, and/or
nucleic acids, and self-encoded molecular beacons of ‘cell stress’ or danger. The consequent innate e ector
mechanisms include activation of complement, enhancement of phagocytosis, and exocytosis by
elimination of the pathogen.
In contrast to the rapidly-activated, generic innate response, the adaptive response is highly-speci c but
delayed. It depends upon the expansion and di erentiation of clones of (thymic-derived) T cells and
(bursa-equivalent) B cells that are selected by the binding of antigen to clonally distributed receptors
produced by seemingly-random somatic gene rearrangement within T-cell and B-cell progenitors
(Kurosawa and Tonegawa, 1982). Following their antigen-driven selection, the activated B cells and T cells
generate di erentiated progeny with e ector function, and additionally commit cells to reservoirs that
retain memory for the eliciting antigens. Whereas T-cell receptors of all progeny stay true to the parental
cell, B-cell (immunoglobulin) receptors undergo somatic mutation of their heavy and light variable (V-)
regions to derive better tting (higher a
nity) receptors, culminating in best- t antibody molecules being
released into the circulation. Antibodies of identical speci cities can be made using distinct Heavy (H-)
chains (classes and subclasses or isotypes) responsible for mediating di erent functions, some of these
being critical to elimination of the organism or neutralization of its key attachment and virulence
molecules, through localizing and amplifying innate mechanisms. Conversely, T-cell receptor structures
are constant, but can be expressed by T cells of di erent e ector potentials, thereby suiting the host
response to the nature of the challenge, as is elaborated on next.
To a rst approximation, the adaptive system uses antibodies to target pathogens that exist outside the
body’s cells but exploits T cells to deal with microbes that reside within cells. In most vertebrates studied in
any detail, the great majority of circulating T-cells bear receptors (TCR) made up of so-called α and β
chains, although this is not the case in, for example, chickens and in cattle during the rst year of life, in
which very many T cells bear TCRs composed of γ and δ chains. Moreover, seemingly in all vertebrates, T
cells that reside within non-lymphoid tissues (e.g. skin and gut), are enriched in γδ T cells distinct from
those in the circulation.
For αβ T cells to recognize intracellular protein antigens, it is necessary for the antigens to be processed into
shorter peptide fragments which are loaded intracellularly into the clefts of major histocompatibility
complex (MHC) Class I or MHC Class II molecules, thereby stabilizing those MHC molecules and their
expression at the cell surface. MHC Class I-associated peptides provide the target for CD8 + T-cellmediated cytotoxicity, while MHC Class II-associated peptides provide the target for CD4 + T cells.
In order for T cells to be activated, it is essential that they see their peptide antigen on activated ‘antigenpresenting cells’, particularly dendritic cells (DC) (Banchereau and Steinman, 1998; Mellman, 2013), which
are specialized forms of innate myelomonocytic cells. Initial and necessary activation or ‘licensing’ of DC
largely occurs through the previously mentioned innate-sensing receptors. Among these, Toll-like
receptors (TLRs) are the best studied (Medzhitov and Janeway, 1997; Beutler and Rehli, 2002). Su
ce it to
say, the sensing of pathogens by engagement of TLRs and/or other equivalent receptors is crucial to the
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
neutrophils, eosinophils, basophils, macrophages, natural killer (NK), γδ T cells, and other cells, all aimed at
licensing of DC that is, in turn, critical for their capacity to activate naïve T cells. Licensing is manifest in an
altered DC phenotype involving, in particular, upregulation of sets of costimulatory molecules such as
CD40, CD80, and CD86. These interact with corresponding receptors on T cells to provide so-called ‘second
signals’ that enable antigen to drive T cell activation. In short, it is the second signal that connects innate
immunity to adaptive immunity. Without such licensing DC, antigen presentation will not only fail to
immunize T cells but may even end up tolerating them. In fact, DC can be ‘decommissioned’ away from this
licensing function in many ways, including exposure to diverse agents such as IL-10, TGFβ, Vitamin D, and
interaction with regulatory T cells (Steinman et al., 2003; Hammer and Ma, 2013).
As was introduced earlier, antigen-speci c CD4+ T cells can di erentiate into subsets with di erent
immune functions. Th1 cells making IFNγ, Th2 cells making IL-4, Th17-cells making IL-17, and T cells
expressing Foxp3 and able to regulate other immune cells. These di erent functional subsets are
interaction with MHC Class II-expressing myelomonocytic cells of which DC are key players. Not only can
DC be licensed by diverse sensors of perturbation, but they can also be activated by CD4+ T cells, as a route
to providing help to enable further cohorts of naïve CD4+ or CD8+ T cells to be recruited into immune
responses (Ridge et al., 1998). Among these, CD8 + T cells are best known for their cytotoxic functions, but
they too can secrete in uential cytokines a ecting their local milieu.
For an adaptive immune response to occur, antigens must gain entry to DC undergoing activation-induced
enhancement of antigen processing and presentation. To facilitate their interactions with (their so-called
‘priming of’) naïve T cells, licensed DC migrate from the tissues, within which they were exposed to
pathogens, moving to draining lymphoid tissues, wherein they promote the clonal proliferation and
di erentiation of those T cells with TCRs speci c for the antigens presented by the licensed DC Thereafter,
primed T cells re-enter the circulation, with some making their way to the peripheral sites where the
initiating antigens are located. The clues that direct them to the correct locations arise from the
in ammation evoked by the infection. Local in ammation induces the neighbouring post-capillary venules
to upregulate distinct patterns of adhesion molecules (as if barcodes) which can divert the recently activated
T cells and other leukocytes out of the circulation at that site and no other. Leukocytes with di erent
functions perceive di erent barcodes, so determining the functional composition of white cells entering the
tissue. The nature of the infective agent is indeed in uential in determining what barcodes are exhibited on
the endothelium. Once in the tissues, both CD4+ and CD8+ T cells can liberate in uential cytokines, interact
with tissue-resident and other tissue-in ltrating immune cells, and deliver protective functions. Altruistic
self-sacri ce of virally infected tissue cells that can be easily replenished provides an e ective way to
eliminate pathogens.
While a proportion of T cells are recruited to peripheral tissues, others may be retained in the lymphoid
tissues, as in the case of some CD4 helper T cells that localize to germinal centres where they provide
cytokines to help antigen-speci c B cells generate antibodies. Other CD4 + and CD8 + T cells may
di erentiate as memory cells, using their own particular barcodes to locate to sites appropriate for their
role.
p. 332
These steps to achieve bene cial pathogen-directed immunity can be considered as necessary stages for
virtually all forms of adaptive immunity associated with αβ T cells.
As might be expected, the immune system has inbuilt checks and balances to prevent in ammationgenerating immunity getting out of hand. In part, this is achieved by a wide range of co-inhibitory
molecules that counter secondary signals induced by licensed DC (Chambers and Allison, 1999). The best
known of these are CTLA4 and PDL1, molecules which have been extensively studied in their capacity as
‘checkpoint inhibitors’. Understanding the circumstances where co-inhibition dominates costimulation
o ers a major theme in cancer immunology.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
responsible for orchestrating and sculpting the behaviour of diverse cellular elements through their
Whereas most αβ T cells provide the means to monitor speci c intracellular microbes by their response to
processed peptide antigens presented by MHC, other αβ T cells can sense microbial lipids presented by a set
of MHC-related molecules, known collectively as CD1. Moreover, the repertoire of moieties sensed by T cells
is increased further by γδ T cells whose recognition is not limited to either MHC or CD1-associated antigens.
Furthermore, activation of γδ T cells does not necessarily require elaborate antigen processing, and
presentation, and consequent clonal outgrowths. Consequently, γδ T cells are not limited to the delayed
adaptive response mode of αβ T cells. Indeed γδ T-cell recognition of self-encoded beacons of cell and tissue
dysregulation (Willcox et al., 2012) can provide a rapid mechanism for the immune system to eliminate
stressed cells in tissues, such as those infected by pathogens, or those subject to carcinogens (Willcox et al.,
2012; Vantourout and Hayday, 2013). Thus, γδ T cells illustrate how some lymphocytes can contribute both
to the early innate phase and to the delayed adaptive phase of an immune response. The same may be true of
innate-like lymphocytes resident within tissues impacts upon the temporal progression of the immune
response through its innate and adaptive phases, and the development of antigen-speci c memory.
Relevance of antipathogen immunity to cancer immunology
Given the necessary stages required for T cells to become activated, to deliver e ector functions, and to
generate challenge-speci c memory, what would be needed for tumour antigens to achieve the same
outcome?
The necessary elements would be:
1. antigens to which T cells with cognate TCRs are available in the circulating immune repertoire;
2. appropriate molecular signals of cell/tissue perturbation to license dendritic cells;
3. absence of tumour-associated elements that might interfere with licensing, or even decommission
DC;
4. adequate bar-coding of primed T cells to permit their homing to sites of tumour growth and to sites of
memory reservoirs;
5. receptiveness of the tumour and its vasculature to entry of primed T cells;
6. a tumour-associated environment (TAM) that enables the e ector T cells to express their full e ector
potentials.
Failures in routinely delivering destructive immunity to cancers suggests constraints at one or more of
these levels. A major theme of modern cancer is to identify routes to bypass any, or all, of these constraints.
Self-tolerance and its relationship to cancer
The immune system adopts three general strategies to minimize reactivity to ‘self’
The rst involves tolerising self-reactive lymphocytes as they develop in the primary lymphoid organs. For
T cells this happens in the thymus, and for B cells largely in the bone marrow. Remarkably the thymic
medullary epithelial cells, through the function of the Autoimmune Regulator transcription factor AIRE,
promiscuously express a vast array of self-proteins and their processed peptides, enabling a massive
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
some subsets of B cells. Importantly, we currently lack an understanding of how the responses of such
purging of the antiself T cells that engage them at this staging post (Anderson and Su, 2016; Richards et al.,
2016).
Simultaneously, the actions of another transcription factor (Foxp3) expressed in some CD4 + T cells can
rescue T cells with antiself reactivity while endowing them with a protective regulatory function (Hori et al.,
2003; Ramsdell and Ziegler, 2014). These natural or thymic regulatory T cells (tTreg) seem critical for selftolerance, as their absence in humans and mice can result in severe multisystem autoimmune disease.
Clearly, promiscuous gene expression through AIRE does not ensure su
cient clonal deletion to protect
against all autoimmunity. This suggests that any residual self-reactive T cells spared from clonal deletion
are likely held in check by the action of Treg.
The antigen-dose-sensitivity of B cells to clonal deletion appears less than that of T cells (Chiller et al., 1971;
inactivated during development, whereas those against sparse self-antigens may be spared. As B cells need
T-cell help to generate antibody responses (Mitchell and Miller, 1968), and as any potential antiself helper
cells are normally deleted, T-cell-independent B-cell autoimmunity is unlikely. Whenever IgG
autoantibodies arise, there must always have been an antecedent CD4 + helper T-cell response to an antigen
(Fig. 23.1)
Fig. 23.1
T cells become tolerant to most self-antigens during their development in the thymus. Expression of the AIRE gene in thymic
medullary epithelial cells results in promiscuous expression of the majority of self-proteins with each medullary cell expressing a
small proportion of such antigens, while the whole population provide coverage for all. Whether these antigens are expressed on
the epithelium or reprocessed by dendritic cells, the outcome is the deletion of most self-reactive T cells. Some self-MHC
restricted CD4 T cells, which come to express the transcription factor FoxP3, are not deleted, and emerge from the thymus as
regulatory T cells, that provide an additional failsafe against autoimmune disease.
The second category of tolerance processes, known as ‘peripheral tolerance’ embraces several mechanisms
(Mueller, 2010). For example, a T cell seeing its antigen in the absence of other triggering signals may be
inactivated or die, or even become outnumbered by lymphocytes that regulate immune function. The best
studied regulatory lymphocytes are CD4 + Treg, some of which (tTreg) arise in the thymus, as previously
mentioned, while other Treg are induced de-novo in tissue microenvironments rich in TGFβ and/or lacking
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Goodnow and Basten, 1989). This means that B cells against abundant, ubiquitous antigens are deleted or
pro in ammatory mediators, or in circumstances of mTOR inhibition (Chen and Konkel, 2010; Waldmann et
al., 2016). Intimately involved in dictating these pathways are diverse tissue-in ltrating myelomonocytic
cells-including monocytes, granulocytes, and the heterogenous population of myeloid suppressor cells
(MSDC; see Gabrilovich et al., 2012; Marvel and Gabrilovich, 2015); tumour-induced endothelial cells and
other stromal elements (Quail and Joyce, 2013; Joyce and Fearon, 2015); and innate-like tissue-resident
lymphocytes (Hayday and Tigelaar, 2003).
Third, and rarely discussed, are the range of ‘silent’ events in normal or healing tissues that discourage or
p. 333
curtail immune
reactivity. It is quite likely, given the di erent physiological demands on di erent
tissues, that each might use di erent mechanisms to ensure that immune responses to eliminate microbes
do not get out of hand and cause irreparable tissue damage. At the extreme end of these are tissues,
identi ed from transplantation research, wherein immune responses are vigorously constrained. These
eye, and to a lesser extent, brain, testis, and ovaries are the best known (Stein-Streilein and Streilein, 2002;
Simpson, 2006). Almost certainly all tissues will, through a coordinated activity of their diverse cellular
components, create molecular environments that limit immune activity within them. Equally tissues in the
process of healing and remodelling provide many negative feedback signals, of which local active TGFβ
inducing immunosuppressive adenosine-generating ectonucleotidases on many tissue cells provides one
good example (Regateiro et al., 2011).
Tolerogenic processes can also be promoted in circumstances where some immune activation has already
occurred. These have been highlighted in the analysis of experimental animals, where foreign tissues have
been accepted long term (Baas et al., 2016; Waldmann et al., 2016), and in reversal of organ-speci c
autoimmune diseases, after short term therapeutic intervention (Chatenoud et al., 1997). Studies of the
tissue components in these situations have emphasized a role for newly established microenvironments
within such tissues, whereby cross talk between innate, adaptive immune cells as well as tissue cells renders
the tissue less permissive for immune attack.
Collectively, these examples of the tissue ‘ ghting back’ can be considered as forms of acquired
immunological privilege.
Research into mechanisms of natural and acquired privilege provides information on the diversity of
protective tissue reactions that can operate. On the one hand, these may re ect the directions any given
tissue can follow to sculpt the immune in ltrates within it to ensure damage limitation. On the other hand,
they may give clues on the ingredients that tumours use to achieve the same outcome. In short, the study of
immune interactions with tumours has lots to learn from the study of immune interactions with normal
tissues, and vice versa.
In fact, the analysis of how the tumour microenvironment allows tumours to escape T-cell damage is now
o ering the most rapidly advancing evidence for privilege mechanisms in general. Undoubtedly, its
understanding will have broad rami cations, not only in the treatment of cancer, but also in reversal of
autoimmune diseases, the prevention of allogeneic cell and organ rejection, and the limitation of major
in ammatory diseases.
The combined knowledge emerging from all these directions, and especially from cancer studies, challenges
the view of immunity and tolerance as binary discrete processes. Elements of each are always contributing
to the way that the immune system reacts to antigen encounter. What we call an immune response, is one
that emerges despite many constraining in uences, whereas when we speak of tolerance to tumours, we are
recognizing that tolerance mechanisms have simply prevailed over immune ones that were present but that
passed unnoticed.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
have been referred to ‘immunologically privileged sites’, of which the placenta and anterior chamber of the
Cells hitherto thought of as mediators of immunity, can, in particular contexts, also behave as mediators of
tolerance and vice versa (Wang et al., 2010). The mere enumeration of cell types in biopsy cannot tell us
whether the immune in ltrate is an indicator of imminent destruction or of protection. More detailed
p. 334
parameters of cell
subpopulations, their relative proportions, their micro-anatomical locations,
frequencies of discrete cell-cell interactions, and indicators of their functional capacity, are all relevant in
what has come to be called the analysis of cell ‘contexture’ as a guide to cancer prognosis and treatment
(Fridman et al., 2012; Galon et al., 2013; Gentles et al., 2015; Galon et al., 2016).
The acceptance of the notion, that most of our well-studied cells of the innate and adaptive immune system,
can be a force for tumour rejection as well as for tumour acceptance, is key to therapeutic intervention in a
way appropriate to the patient’s tumour. Despite, the possible diversity of tolerance-related mechanisms
operating we need, to establish priority lists of the most generic and tractable of these that can be targeted,
o er a commercial incentive to their manufacturer, and duciary practicality to healthcare providers.
Why do we think that tumours may have antigens the immune system
can target?
Evidence for immunosurveillance of cancer
It has long been known that some cancer patients undergo spontaneous remissions of their disease. Patients
receiving ‘immunosuppressive’ drugs to prevent graft rejection are more susceptible to diverse cancers.
Some cancers are clearly caused by oncogenic viruses (e.g. human papilloma virus (HPV), EBV, or hepatitis),
but others seem not to be. The possibility that immune mechanisms might have been involved in control of
cancer was recognized some 60 years ago, when it was shown that chemically induced tumours could be
rejected in inbred mouse strains. These and related experimental ndings spawned the notion of cancer
immunosurveillance proposed by Burnet (Dunn et al., 2004). It was initially somewhat discouraging that Tcell de cient mice did not show a higher susceptibility to chemically–induced cancers compared to their
normal counterparts, although their increased susceptibility to tumours caused by polyoma virus was
consistent with immunosurveillance (Simpson and Nehlsen, 1971). However, later evidence that
neutralization of IFNγ by antibodies enhanced tumour growth, and that IFNγ de cient mice were more
susceptible to tumours, restored optimism to the concept of immunosurveillance, further boosted by clear
evidence that mice de cient speci cally in γδ T cells have heightened sensitivity to environmental
carcinogens (Girardi et al., 2001). Likewise, tumour incidence is higher in mice in which elements of the Tcell killing machinery and members of the TNF family were compromised.
Later work showed that tumours developing in immunocompromised mice demonstrated greater
immunogenicity when transferred into fresh immunocompetent hosts, than those developing in controls.
This observation led to the immunoediting hypothesis (Dunn et al., 2004), a modi cation of the original
immunosurveillance theory. Here it was envisaged that the interaction of the immune system with cancers
operates in three phases: elimination, equilibrium, and escape. Although no experiment has de nitely
established that this hypothesis satisfactorily re ects a general facet of cancer biology, it provides a useful
framework for considering how the immune system may interact with tumours, and hence how the balance
may be swung toward tumour eradication and patient bene t. ‘Elimination’ re ects the capacity of innate
and adaptive mechanisms to clear early tumour cells. Should this fail, then the ‘equilibrium’ phase re ects
the capacity of T cells to keep the tumour under control. When that eventually fails for whatever reason,
tumours enter the ‘escape’ phase. The proposed equilibrium phase o ers a period during which the immune
system exerts pressure on tumours to develop escape mutants. Many tumours at time of presentation are
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
rather than aiming at treatments that become too personalized. Ultimately, our chosen drugs will need to
likely to be in this proposed escape period. Identifying the reasons for tumour escape may o er therapeutic
routes to its prevention.
As mentioned, evidence supporting the immunoediting idea has been provided from chemically induced and
spontaneous tumours in mice, based on identifying changes in immunogenic antigens. In recent years,
abundant data from human tumours has been consistent with a role for the immune system in shaping
tumour evolution. Analysis of the quality, location, and intensity of immune in ltrates in tumours has
provided prognostic information for tumour outcomes with a series of Th1 related indicators proving a more
favourable prognosis for many tumours. Surprisingly, ‘signatures’ re ecting Th2-like, Th17, or regulatory
T-cell signatures have not been so clear cut. Perhaps consistent with the mouse data mentioned earlier, a γδ
T-cell signature has proved to be the strongest correlate of overall survival in an unprecedentedly large
survey of 18,000 patients (Gentles et al., 2015). Understandably, many attempts are currently being made to
tumour outcome (Galon et al., 2016; Mlecnik et al., 2016).
The nature of tumour antigens
Early evidence for immunogenic tumour-associated antigens came from serology of individuals bearing
tumours, and in paraneoplastic immune disorders with antitumour antibodies detecting shared antigens on
neuronal cells. Although indicative of adaptive immunity, little evidence existed on whether the response
was driven by self-antigens, or neoantigens, derived from altered self-proteins encoded by genes mutated
by genotoxic carcinogens. Spontaneous antitumour T-cell responses (both CD4+ and CD8+ T cells) have
been identi ed in some patients with melanoma, and as mentioned earlier, these examples give indications
that the host may be able to mount response to self-antigens in tumours, where perhaps clonal deletion had
not occurred.
Virally induced tumours (e.g. EBV, HPV, hepatitis virus) all o er potential tumour-associated antigens that
are ‘foreign’, to which the host will not be naturally tolerant. The natural CD8 T-cell mediated immunesurveillance that prohibits malignant B-cell accumulation in most EBV infected people is a good indicator
that antiviral immunity enables a long-term equilibrium between host and cells harbouring the oncogenic
virus.
However, the most compelling evidence that neoantigens emerge in cancers, that these are subject to
immune attack, and that they change over the time course of tumour development, comes from advances
using modern DNA recombinant technologies involving exome sequencing of tumours and T cells
in ltrating them, in-silico extrapolations of whether peptides predicted to derive from mutated proteins
are potential immunogens able to bind to MHC molecules, and technologies to show that T cells can bind
p. 335
these and become
activated (Linnemann et al., 2014; Gubin et al., 2015; McGranahan et al., 2016;
Schumacher and Schreiber, 2015; Ward et al., 2016). After successful studies in mouse cancer models, such
technology is now being applied to human cancers, albeit with a propensity of studies largely, thus far,
con ned to melanoma (Fig. 23.2).
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
take many of the immune parameters into account in providing an ‘immunoscore’ to predict the potential
Fig. 23.2
Source: data from Schumacher TN and Schreiber RD, ʻNeoantigens in cancer immunotherapyʼ, Science, Volume 348, Issue 6230,
pp. 69–74, Copyright © 2015 American Association for the Advancement of Science.
Many neoantigens have now been identi ed that bind to both MHC Class I and II molecules. It is also clear
that some tumours exhibit a high mutational load, and others less so. The expectation is that those with a
higher mutational load will generate more neoantigens. There is now the opportunity to pool such
information with that of the contexture scores, as well as therapeutic outcomes to assess the impact of
neoantigenic load on outcomes of therapy (Rizvi et al., 2015). As expected, given the stochastic nature of
mutational neoantigens, it may be di
cult to nd broadly-shared antigens within tumour types. That,
together with MHC polymorphisms may make it di
cult to identify worthwhile tumour-vaccine
candidates, other than on a personalized basis. In the context of personalized therapies (if such were
commercially viable), knowledge of an individual’s neoantigen repertoire may enable selection and
expansion of antigen-speci c cells from those in ltrating the tumour, or engineering of T cells to express
TCRs recognizing such antigens for adoptive immunotherapy.
A word of caution though! These aspirations may be confounded by limitations imposed by the patient’s
available TCR repertoire, as well as our lack of knowledge of how both qualitative and quantitative
MHC/peptide epitope expression at the cell surface determines immunogenicity.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Identification of cancer neoantigens. Ribonucleic acid (RNA) sequencing of tumour extracts RNA sequencing data enables
detection of mutations in expressed genes. Likely mutated peptides are catalogued, and those likely to bind to MHC Class I are
predicted and tested for possible immunogenicity in in vitro functional assays. Similar approaches are used to detect MHC Class
II binding neoantigens that stimulate CD4 + T cells.
The demonstration of tumour-specific T cells in tumours
The strategy for studying T cells in ltrating tumours owes much to early studies of adoptive T-cell
transferred from mice immunized to tumour antigens. Poor protection was initially observed until transfers
were attempted into lymphocyte-depleted recipients. Pioneering studies by Rosenberg using extracted
human melanoma in ltrating lymphocytes expanded in culture with IL-2, and transferred into
lymphocyte-depleted patients provided evidence that these cells could attack the cancer and persist in the
circulation (Rosenberg and Restifo, 2015; Topalian et al., 2015). The necessity for prior host lymphocyte
depletion for e
cacy could re ect a need for homeostatic cytokines and ‘space’ to enable transfused
lymphocytes to expand further and di erentiate, or relate to, ablation of other immune inhibitory pathways
operating in the lymphocyte-replete host.
mutated antigens. Studies with epithelial cancers, using exomic sequencing to identify possible
neoantigens, have provide evidence that TILs include T cells responsive to some of these neoantigens. Once
expanded in vitro, some such TILs could achieve dramatic tumour regression on transfer (Hinrichs and
Rosenberg, 2014; Rosenberg and Restifo, 2015). Another approach to identify reactive T cells has been to
engineer their receptors (TCR) so that they can be transfected into naïve T cells to give them target
p. 336
speci city (Rosenberg and Restifo, 2015). In
some examples using TCRs to non-mutated antigens, where
cancer regressions were observed, damage to other normal tissues could also be seen, indicating broader
display of those antigens beyond the tumour itself. Somehow, the host from which such TILs had been
derived, had not exhibited such o -target damage-perhaps pointing to protective regulatory processes
operating to limit damage. Nonetheless, it is the case that some melanoma patients with immune responses
to their tumours present clinically with vitiligo in normal areas of skin.
How do tumours provide the innate signalling mechanisms in the way
that microbial pathogens do?
It is now widely acknowledged that there exist a large range of mechanisms for sensing cell stress, damage,
and death, which can provide adjuvanticity for tumour antigens, in the way that PAMPS do for microbial
antigens. These damage-associated molecular patterns (DAMPs) are distinct entities but can engage in
much cross talk with PAMP signalling mechanisms. A detailed understanding of DAMPS and their signalling
pathways will be an important avenue of future research aimed at maximizing the immune response to
tumour antigens (Schaefer, 2014; Woo et al., 2015).
The tumour-associated microenvironment limits immune activity
against tumour antigens
The accumulating evidence, that some tumours contain T cells with speci city to tumour neoantigens,
raises the question of why these are not eradicating the tumour. A compelling answer to this question has
recently been provided by the massive and e ective immune response to some tumours unleashed by
blockade of known co-inhibitory molecules such as PD1 or CTLA4 expressed on T cells. These ndings,
together with previously mentioned prognostic studies on the nature of tumour in ltrates, have clearly
indicated that the tumour-associated microenvironment, shaped both by the tumour and by immune
components, determines the extent to which T cells can exert their antitumour potential. As each
contributor is de ned, then additional novel targets for checkpoint blockade become available.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
These studies with TILs have con rmed that melanomas contain T cells that recognize both ‘self’ as well as
Cells in ltrating tumours may have the potential to contribute to tumour damage, but this may be
outweighed by other contributions to contribute tumour growth, and to immune privilege (Hanahan and
Coussens, 2012; Hagerling et al., 2015; Joyce and Fearon, 2015; Marvel and Gabrilovich, 2015; Quail and
Joyce, 2013). Growth promotion may be mediated by diverse growth factors, and proteolytic enzymes that
might alter the extracellular matrix may permit tumour cell spread. Cell sources contributing such in uence
are not limited to leukocytes but may also include tumour-associated broblasts and blood vessels, for
example.
As indicated earlier, T-cell priming requires licensing and migration of antigen-presenting cell (APC).
There is much evidence to indicate that DC isolated from human tumours are functionally impaired, if not
decommissioned. Various products in the TAM have been implicated, including cytokines such as TGFβ, IL10, and vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (MCSF), and even
Even if T cells have been primed, they need to gain access to tumour cells. This requires that they gain entry
through the tumour vasculature and migrate along chemotactic gradients to their targets. Failure of tumour
vasculature endothelial cells to properly coordinate expression of key adhesion molecules is one element to
tumour protection. VEGF, endothelins, and nitric oxide have been implicated as key mediators at this
checkpoint, in addition to a number of well established immunosuppressive molecules.
Beyond the endothelium there are many other cell types that can prevent immune engagement, including
Treg, myeloid-derived suppressor cells (Gabrilovich et al., 2012; Marvel and Gabrilovich, 2015), and
monocytes that are ‘alternatively activated’ as if exposed to Th2 T-cell products (Hanahan and Coussens,
2012). Some of these e ects on e ector T cells can be mediated by enzymes catabolizing among others,
tryptophan (Munn and Mellor), and L-arginine (Molon et al., 2011) creating a nutrient-deprived local
microenvironment, and generating range of anti-in ammatory moieties, such as kynurenines, active
radicals of oxygen and nitric oxide, and peroxynitrite. Peroxynitration and inactivation (by
nitration/nitrosylation) of chemokines and cancer neoantigens is one proposed mechanism by which
products of arginine metabolism can impede immune functions. All these factors in uence the balance of
cell types that accumulate in tumours, and the quality of immune privilege that results.
Analysis of the components of the tumour microenvironments indicate widespread cross talk between
cancer cells, their stroma, and the immune system (Fig. 23.3). Evidence is accumulating that diverse
signalling pathways in uencing tissue development and carcinogenesis (e.g. Wnt; see Yamabuki et al., 2007;
Sato et al., 2010), as well as tumour suppression (e.g. p53, PTEN, RB1, and ARF; Munoz-Fontela et al., 2016),
have profound local immune subversive functions in addition to their cell intrinsic functions.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
hypoxia, in some cases associated with enhanced expression of the co-inhibitory molecule PDL1.
Fig. 23.3
Reproduced with permission from Joyce JA and Fearon DT, ʻT cell exclusion, immune privilege, and the tumor
microenvironmentʼ, Science, Volume 348, Issue 6230, pp. 74–80, Copyright © 20152015 American Association for the
Advancement of Science.
It is possible that, in the not-distant future, tumour biopsies can be described by a multidisciplinary readout of cell composition, interactions, and molecules present, that can be interpreted for prognostic outcome
and selection of optimal treatment protocols to promote immunological control (Bindea et al., 2013). At this
stage, however, the goal should be to identify the more critical parameters lending themselves to
therapeutic decisions.
To this end, the identi cation of cell expressing co-inhibitory molecules and their ligands in tumour and
in ltrating cells (e.g. T cells expressing PD1 and Treg expressing CTLA4) and diverse cells expressing PDL1,
o ers some indication as to which tumours might be responsive to checkpoint inhibition with anti-CTLA4
and anti-PD1 antibodies (Mahoney et al., 2015; Smyth et al., 2016). In this arena, there is much need for
improved reagents and standardized protocols.
In the same vein, there may be other less well-documented interactions that may provide biomarker clues
for intervention. These could include indicators for costimulation with agonist antibodies such as TNFR
family members, antibodies to Wnt ligand members (Sato et al., 2010), drugs in uencing TGFβ signalling,
and those targeting (immunosuppressive) adenosine-generating ectonucleotidases CD39, CD73 in diverse
p. 337
immune and epithelial cells (Regateiro et al., 2011; Young et al., 2016), and the upregulation
of these by
TGFβ, o er further opportunities for another type of checkpoint blockade.
The overall principles underlying tumour immunity and its natural resistance are summarized in Figure
23.4 (Chen and Mellman, 2013).
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
(A–F) Mechanisms of immune suppression within the tumour microenvironment. Diverse cellular components in the tumour
microenvironment regulate the entry, accumulation, activation, and expansion of T cells in tumours exemplified in the
representative frames shown.
Fig. 23.4
Reproduced with permission from Chen DS and Mellman I, ʻOncology meets immunology: the cancer-immunity cycleʼ, Immunity,
Volume 39, pp. 1–10, Copyright © 2013 Elsevier Inc. https://www.sciencedirect.com/science/article/pii/S1074761313002963
Overriding tumour privilege: Immune intervention in cancer
Introductory remarks
It is becoming increasingly clear that many of the currently adopted chemotherapeutic drugs for cancer
a ect the immune system. It is not straightforward to determine how much of the therapeutic bene t
derives from direct drug kill, rather than from e ects on immunoregulatory mechanisms (Zitvogel et al.,
2013; Belvin and Mellman, 2015), but it may be appropriate to consider both e ects when optimizing drug
dosing. Clearly, the pleiotropy of chemotherapeutics o ers potentials for combinatorial synergies with
emerging immunotherapeutic modalities.
In considering strategies involving vaccination or adoptive cell therapy the question arises as to which
antigens could be targeted? In principle these could be self-antigens shared by normal tissues with
attendant risks of debilitating collateral damage; self-antigens shared by normal cells whose loss would not
be a health risk (e.g. melanocytes); self-antigens expressed in ontogeny but not in the mature individual
p. 338
(so-called oncofoetal antigens); and, of course,
tumour neoantigens. Exploitation of the latter may
require personalized therapies with their attendant commercial limitations. Of the various self-antigens,
one category currently attracting attention for this reason are the numerous cancer testis antigens
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Stimulatory and inhibitory factors in the cancer-immunity cycle. The pathway used by the immune system to generate
antitumour immunity (in green). Released tumour antigens are processed by dendritic cells that are licensed by ʻdangerʼ signals
to leave the tissue and make their way to secondary lymphoid tissues. There they filter out antigen reactive lymphocytes from
the circulation and immunize them to the tumour antigens. These ʻselectedʼ T cells migrate out of the lymphoid tissue into the
circulation, some providing memory cells for future encounters, while others make their way into the tumour a er traversing the
local vascular endothelium. If the microenvironment does not impede their activity, they will then go on to damage tumour
cells, release more tumour antigens, and enable the cycle to be perpetuated. For all stages in the cycle there are a myriad of
potentially inhibitory mechanisms (examples in red) that, in the modern era, constitute potential targets for checkpoint
blockade.
(Djureinovic et al., 2016; Li et al., 2016; Park et al., 2016), normally expressed on male germ cells, but
aberrantly expressed on some tumours. Given the potentially tolerable collateral damage some may prove
useful targets, especially for evolving generic strategies to enhance tumour kill.
Vaccination against non-viral cancers
The notion that one might have vaccines against de ned self-antigens is predicated on the fact that central
tolerance is not perfect, and that the autoantigens concerned may not be expressed on vital cells, or cells
that cannot easily be renewed. Any therapeutic vaccine strategy needs to incorporate components that
enable the licensing of dendritic cells, and numerous strategies for doing this have emerged (Palucka and
Banchereau, 2013; Romagnoli et al., 2014; Shimizu et al., 2016). Although there are examples of some
strategy has yet emerged (Melief et al., 2015; van der Burg et al., 2016).
By contrast, the more likely targets for vaccine development should be tumour neoantigens. However, these
would, more often, need to be patient-speci c and hence potentially expensive to develop. In the context of
adoptive cell therapy, there may be a route to identify vaccine-peptides to select and expand TILs from
individual patients for adoptive T-cell therapy.
p. 339
Vaccination against viral cancers
Some 20% of human cancers are known to have an infectious origin. Prophylactic vaccines have emerged
for only two of these (hepatitis B and HPV). Persistent infections with HPV o er a challenge for the
development of a therapeutic vaccine, as the persistent virus needs to be eradicated before cancer develops.
EBV vaccines would be highly desirable given the number of malignancies arising, but no useful vaccine has
yet been demonstrated. Even in the case of HPV best e
cacy data are provided in patients with
premalignant lesions.
In short, our marked inability to overcome many infectious diseases through vaccination, highlights the
huge challenges in developing e
cacious prophylactic vaccines. Those challenges are likely to be greater for
therapeutic vaccines, even where viral non-self-antigens are concerned. On this basis, it will be no easy
matter to immunize cancer patients to eradicate their tumours. The presumption is that even if antigenspeci c responses are induced, the ability of the host to mount e
cacious e ector responses will be limited
by peripheral tolerance mechanisms of the kind discussed earlier. From our knowledge of the adaptive
immune response, the best therapeutic immunization outcomes will most likely come where the vaccines
promote the responses of both antigen-speci c CD4+ T cells as well as CD8+ cells, given in such a way as to
provide strong and sustained licensing of dendritic cells. Moreover, to ensure access of e ector cells to
tumour cells we will need to break open the strangleholds of the tumour microenvironment. This will
undoubtedly require combinatorial therapy based on the emerging knowledge of its organization.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
therapeutic bene t from vaccination to ‘self’ tumour antigens, no really e ective therapeutic vaccine
Therapeutic antibodies
The application of preformed antibodies as magic bullets became a reality when Kohler and Milstein (Kohler
and Milstein, 1975) described the monoclonal antibody technology (Fig. 23.5). The initial optimism was not
immediately realized for many reasons. Many of the initial rodent antibodies (Mabs) were poorly lytic even
for circulating blood cells. Very few were able to utilize the human complement system for killing, while
others were directed to antigens which were simply not disposed to e ective lysis by cell mediated Fc
dependent killing mechanisms. It also became clear that rodent IgG isotypes vary enormously in recruiting
natural lytic mechanisms, with mouse IgG2a and rat IgG2b subclasses being the most e ective. Some
antigens were easily modulated o
the cell surface, and other were simply too sparse. Rodent antibodies
proved immunogenic for man, meaning that they could only be used for a short time. This early pessimism
therapy, but these generated their own problems of unwanted toxicities and additional immunogenicity.
Fig. 23.5
Genetic engineering has been successful in transforming rodent antibodies into human forms that are far less immunogenic. The
technologies that evolved to achieve this have provided a platform which has catalysed the therapeutic exploitation of many
facets of immune function as novel cell-bound, and also, cell-free fusion proteins.
Extensive knowledge of the structure of immunoglobulin genes, and ideas on how antibody diversity was
generated, rapidly enabled the application of genetic engineering technologies to create improved
immunoglobulins that nature had itself never made.
Initially, chimeric antibodies having rodent variable regions and human constant regions allowed for
selection of appropriate IgG isotypes (e.g. IgG1 and IgG3 for most e
cient lysis; see Bruggemann et al.,
1987), and diminished their degree of foreignness to man. Shortly after, Winter and his colleagues (Jones et
al., 1986) demonstrated an even greater degree of humanization by creating antibodies where only the
complementary determining regions remained rodent, so reducing the risk of immunogenicity even further.
These initial observations spawned a revolution in the biotechnology sector, resulting in methods to
generate antigen-speci c human antibodies wholly in silico, or even replacing the rodent immunoglobulin
genes with human (Bruggemann et al., 1989), so that mice could be immunized to generate human
antibodies from the outset.
Even with this technology, the attempts to directly kill cancer cells have been no simple matter, except
perhaps for more easily accessible cancers of the blood system. More recently toxins for conjugation have
been mutated to eliminate potential T and B-cell epitopes, so enabling further e orts to exploit antibodytoxin conjugates (Mazor et al., 2016). Antibodies have also been engineered to be able to deliver
chemotherapeutic drugs more selectively to the tumour site.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
led to early studies with antibody-toxin conjugates, aiming to achieve adequate kill from a short pulse of
Overall though, failure of naked antibodies to achieve an adequate kill of solid tissue malignancies comes
from limitations in tumour penetration, and failure of the Mabs to recruit a su
cient innate e ector
mechanism (for Fc-mediated lysis). O -target toxicities are also real issues sometimes related to the
expression of the target antigen on other body cells.
p. 340
Where human monoclonal antibodies have fared better has been where they have been used to block
inhibitory immune function as checkpoint inhibitors (Ribas and Wolchok, 2018) or alter cell signalling
(Herceptin and Erbitux; see Katsumata et al., 2006), in addition to any immune-mediated mechanisms.
Although combination therapy with other Mabs or therapeutic modalities can give improved outcomes,
there remains a commercial incentive to engineer antibody forms that may be more potent by focussing
multiple e ector moieties, within the one antibody construct to the tumour target. This can be achieved by
appropriate antibody variable regions to target the tumour. Perhaps the best early examples of such
engineering are bispeci c antibodies having one arm directed to the cancer antigen and the other to the CD3
epsilon chain of the TCR (Staerz and Bevan, 1989). This approach theoretically allows any T cell, regardless
of its own antigen speci city, to be recruited and activated to the site of the tumour with demonstrable
e
cacy (Staerz and Bevan, 1989; Riethmuller, 2012). Generation of intracellular antibody fragments to
critical functional sites on oncogenes is proving an exciting route to the generation of novel chemical drugs
blocking interactions of oncogenes with other protein partners in malignant cells (Quevedo, 2018, CruzMigoni.2019).
Adoptive lymphocyte therapy
The previously mentioned work of Rosenberg and colleagues using in vitro antigen expanded TILs, has
demonstrated the potential of adoptive immunotherapy (Rosenberg and Restifo, 2015). Host lymphocyte
depletion was important in allowing the expanded cells to mediate tumour kill.
The unpredictability of tumour antigens coupled with human MHC polymorphisms has rendered such Tcell therapy very personalized, and not ideal for commercial development, even allowing for advances that
might reduce the resistance of the tumour microenvironment.
The ideal adoptive immune cell therapy would be one where the e ector cells recognized and could be
activated and expanded by some endogenous ligand that is reproducibly expressed on tumour cells, and few
normal cells. It is this notion that is driving interest in the possible use of γδ T cells and NKT cells for cancer
immunotherapy (Silva-Santos et al., 2015). The natural propensity for γδ T cells to be resident in tissues may
allow them to access tumours and to perform more e ectively than αβ T cells. Consistent with this view, is
the claim that a γδ T-cell signature local to the tumour is the strongest correlate of overall survival (Gentles
et al., 2015).
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
incorporating multiple non-immunogenic ‘self’ e ector modules in fusion proteins expressing the
Engineering of T cells
As is discussed in other chapters of this book, there has been extensive e orts to enhance the therapeutic
power of adoptively transferred T cells. There are two general categories. The rst involves use of cloned
antigen-speci c TCR genes introduced into human T cells (Johnson et al., 2009; Perro et al., 2010).
Preclinical mouse models may allow selection of the optimal TCRs for therapeutic use (Obenaus et al., 2015).
By their nature these will be MHC restricted and limited to targeting ‘self’ antigens whose o -target
expression runs little risk, or to neoantigens that will likely limit utility to the individual patient. The best
use of such cells will likely involve sets of gene manipulations that increase their sensitivity to antigen
stimulation, limit their ability to be tolerated by their cognate antigen, endow them with adhesion and
chemotactic receptors that o er optimal migration to tumour tissue, enhanced lytic machinery to kill their
stage then, of what sort of ‘o -the-shelf therapies’ will o er the necessary commercial incentive to
developers.
The introduction of antibody variable regions into chimeric TCR-like signalling molecules in T cells (CAR-T
cells; Kalos and June, 2013; Fesnak et al., 2016; Gross and Eshhar, 2016) o ers a more general approach to
target cell surface antigens shared by many individuals. Once again, the most useful target antigens for
these are membrane-exposed di erentiation antigens on cells that are accessible and easily replenished by
the host.
Perhaps not surprising therefore that malignancies of the haemopoietic system are those that have proven
most targetable, thus far.
A major challenge in using third party CAR-T cells is that the host will inevitably reject them. Host
preconditioning of recipients to temporarily prevent rejection might provide a su
cient window for the
cells to expand, deliver, and their kill, so potentially rendering CAR-T cells as o -the-shelf-therapies.
Another major challenge in CAR-T and in checkpoint blockade approaches is to avoid a cytokine storm and
rampant immunopathology initiations where large numbers of de-repressed, primed T cells ood the body
with an excess of immune e ector molecules.
Conclusion
Cancer immunology is in a challenging phase and the major requirements to building on the therapeutic
successes thus far are reported in the ‘Open Questions’. Overall, there remain many challenges. Yet, the eld
is in far better shape than it was 20 years ago. Then, cancer immunology was deemed to be a potential
graveyard for the young immunologist. How things have changed!
Acknowledgements
I am indebted to Adrian Hayday and Elizabeth Simpson for their expert comments and many helpful
suggestions on the manuscript.
Take-home message
• In recent years, advancement in the eld of tumour immunology have started to produce
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
target, and provide them with the where-with-all to be ‘suicided’, if need be. It remains unclear, at this
a range of new therapeutic strategies.
• The notion that tumours can simply ‘escape’ the immune system has changed. It is now
established that some tumours can evoke and/or provide su
ciently adjuvant-like
signals which, if adequately sensed, can promote immune reactivity in the host.
• Cross talk between tumours, stroma, and immune system however can result into an
inhibition of the immune response.
• Hence one of the aims of treatment is to override this inhibition of the immune
response.
Open questions
• Establishing safer and more e ective ways to license dendritic cells to achieve high
quality antigen presentation. Put another way, immunologists have still not cracked the
goals of achieving super-adjuvants that are safe.
• To break open diverse types of tumour microenvironments that limit access of T cells
and antibodies that could be far more tumoricidal were more of them to get to the right
place.
• The need to identify ways of stimulating and empowering host T cells and other innate
cells without depending on identifying neoantigens, as discussed in relation to γδ T cells
and stress surveillance (Hayday, 2009).
• Inevitably, the application of combinatorial therapies will make in-roads (Mahoney et
al., 2015; Sharma and Allison, 2015; Khalil et al., 2016), but it would be valuable to have
some sort of biomarker-based algorithms that might predict the best agents to put
together for individual patients.
• For therapies directed to self-antigens, it will be imperative to establish procedures to
minimize autoimmune damage to normal tissues.
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
p. 341
Further reading
Baumeister, S. H., Freeman, G. J., Drano , G., & Sharpe, A. H. (2016). Coinhibitory pathways in immunotherapy for cancer. Annu
Rev Immunol, 34, 539–73. 10.1146/annurev-immunol-032414-112049
Google Scholar
WorldCat
Crossref
Chen, D. S. & Mellman, I. (2013). Oncology meets immunology: the cancer-immunity cycle. Immunity, 39, 1–
10. 10.1016/j.immuni.2013.07.012
Google Scholar
WorldCat
Crossref
Fredriksen, T., Lafontaine, L., Berger, A., et al. (2013). Spatiotemporal dynamics of intratumoral immune cells reveal the immune
landscape in human cancer. Immunity, 39, 782–95. 10.1016/j.immuni.2013.10.003
Google Scholar
WorldCat
Crossref
Joyce, J. A. & Fearon, D. T. (2015). T cell exclusion, immune privilege, and the tumor microenvironment. Science, 348, 74–
80. 10.1126/science.aaa6204
Google Scholar
WorldCat
Crossref
Palucka, K. & Banchereau, J. (2013). Dendritic-cell-based therapeutic cancer vaccines. Immunity, 39, 38–
48. 10.1016/j.immuni.2013.07.004
Google Scholar
WorldCat
Crossref
Prendergast, G. & Ja ee, E. (eds) (2013). Cancer Immunotherapy. Cambridge, MA: Elsevier Inc.
Google Scholar
Google Preview
WorldCat
COPAC
Quevedo, C.E., Cruz-Migoni, A., Bedry, N., et al. 2018. Small molecule inhibitors of RAS-e ector protein interactions derived using
an intracellular antibody fragment. Nat Commun, 9, 3169. 10.1038/s41467-018-05707-2
Google Scholar
WorldCat
Crossref
Web of Science
Rabbitts, T.H., and Stocks, M.R. 2003. Chromosomal translocation products engender new intracellular therapeutic
technologies. Nat Med, 9, 383–6. 10.1038/nm0403-383
Google Scholar
WorldCat
Crossref
PubMed
Web of Science
Rosenberg, S. A. & Restifo, N. P. (2015). Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348,
62–8. 10.1126/science.aaa4967
Google Scholar
WorldCat
Crossref
Schumacher, T. N. & Schreiber, R. D. (2015). Neoantigens in cancer immunotherapy. Science, 348, 69–
74. 10.1126/science.aaa4971
Google Scholar
WorldCat
Crossref
Sharma, P. & Allison, J. P. (2015). Immune checkpoint targeting in cancer therapy: toward combination strategies with curative
potential. Cell, 161, 205–14. 10.1016/j.cell.2015.03.030
Google Scholar
WorldCat
Crossref
Silva-Santos, B., Serre, K., & Norell, H. (2015). Gammadelta T cells in cancer. Nat Rev Immunol, 15, 683–91. 10.1038/nri3904
Google Scholar
WorldCat
Crossref
Zitvogel, L., Galluzzi, L., Smyth, M. J., & Kroemer, G. (2013). Mechanism of action of conventional and targeted anticancer
therapies: reinstating immunosurveillance. Immunity, 39, 74–88. 10.1016/j.immuni.2013.06.014
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Cruz-Migoni, A., Canning, P., Quevedo, C.E., et al. C. 2019. Structure-based development of new RAS-e ector inhibitors from a
combination of active and inactive RAS-binding compounds. Proc Natl Acad Sci, U S A. 10.1073/pnas.1811360116
Google Scholar
WorldCat
Crossref
Crossref
WorldCat
Google Scholar
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
References
Anderson, M. S. & Su, M. A. (2016). AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol, 16, 247–
58. 10.1038/nri.2016.9
Google Scholar
WorldCat
Crossref
Baas, M., Besancon, A., Goncalves, T., et al. (2016). TGFbeta-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell
anergy in transplant tolerance. Elife, 5, e08133. 10.7554/eLife.08133
Google Scholar
WorldCat
Crossref
Banchereau, J. & Steinman, R. M. (1998). Dendritic cells and the control of immunity. Nature, 392, 245–52. 10.1038/32588
Google Scholar
WorldCat
Crossref
PubMed
Beutler, B. & Rehli, M. (2002). Evolution of the TIR, tolls and TLRs: functional inferences from computational biology. Curr Top
Microbiol Immunol, 270, 1–21.
Google Scholar
WorldCat
PubMed
Bindea, G., Mlecnik, B., Tosolini, M., et al. (2013). Spatiotemporal dynamics of intratumoral immune cells reveal the immune
landscape in human cancer. Immunity, 39, 782–95. 10.1016/j.immuni.2013.10.003
Google Scholar
WorldCat
Crossref
Bruggemann, M., Caskey, H. M., Teale, C., et al. (1989). A repertoire of monoclonal antibodies with human heavy chains from
transgenic mice. Proc Natl Acad Sci U S A, 86, 6709–13. 10.1073/pnas.86.17.6709
Google Scholar
WorldCat
Crossref
PubMed
Bruggemann, M., Williams, G. T., Bindon, C. I., et al. (1987). Comparison of the e ector functions of human immunoglobulins
using a matched set of chimeric antibodies. J Exp Med, 166, 1351–61. 10.1084/jem.166.5.1351
Google Scholar
WorldCat
Crossref
PubMed
Chambers, C. A. & Allison, J. P. (1999). Costimulatory regulation of T cell function. Curr Opin Cell Biol, 11, 203–10. 10.1016/S09550674(99)80027-1
Google Scholar
WorldCat
Crossref
PubMed
Chatenoud, L., Primo, J., & Bach, J. F. (1997). CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J
Immunol, 158, 2947–54.
Google Scholar
WorldCat
PubMed
Chen, D. S. & Mellman, I. (2013). Oncology meets immunology: the cancer-immunity cycle. Immunity, 39, 1–
10. 10.1016/j.immuni.2013.07.012
Google Scholar
WorldCat
Crossref
Chen, W. & Konkel, J. E. (2010). TGF-beta and ʻadaptiveʼ Foxp3(+) regulatory T cells. J Mol Cell Biol, 2, 30–6. 10.1093/jmcb/mjp004
Google Scholar
WorldCat
Crossref
PubMed
Chiller, J. M., Habicht, G. S., & Weigle, W. O. (1971). Kinetic di erences in unresponsiveness of thymus and bone marrow cells.
Science, 171, 813–15. 10.1126/science.171.3973.813
Google Scholar
WorldCat
Crossref
PubMed
Djureinovic, D., Hallstrom, B. M., Horie, M., et al. (2016). Profiling cancer testis antigens in non-small-cell lung cancer. JCI Insight,
1, e86837. 10.1172/jci.insight.86837
Google Scholar
WorldCat
Crossref
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Belvin, M. & Mellman, I. (2015). Is all cancer therapy immunotherapy? Sci Transl Med, 7, 315fs348. 10.1126/scitranslmed.aad7661
Google Scholar
WorldCat
Crossref
Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004). The immunobiology of cancer immunosurveillance and immunoediting.
Immunity, 21, 137–48. 10.1016/j.immuni.2004.07.017
Google Scholar
WorldCat
Crossref
PubMed
Fesnak, A. D., June, C. H., & Levine, B. L. (2016). Engineered T cells: the promise and challenges of cancer immunotherapy. Nat
Rev Cancer, 16, 566–81. 10.1038/nrc.2016.97
Google Scholar
WorldCat
Crossref
Fridman, W. H., Pages, F., Sautes-Fridman, C., & Galon, J. (2012). The immune contexture in human tumours: impact on clinical
outcome. Nat Rev Cancer, 12, 298–306. 10.1038/nrc3245
Google Scholar
WorldCat
Crossref
Galon, J., Angell, H. K., Bedognetti, D., & Marincola, F. M. (2013). The continuum of cancer immunosurveillance: prognostic,
predictive, and mechanistic signatures. Immunity, 39, 11–26. 10.1016/j.immuni.2013.07.008
Google Scholar
WorldCat
Crossref
Galon, J., Fox, B. A., Bifulco, C. B., et al. (2016). Immunoscore and immunoprofiling in cancer: an update from the melanoma and
immunotherapy bridge 2015. J Transl Med, 14, 273. 10.1186/s12967-016-1029-z
Google Scholar
WorldCat
Crossref
p. 342
Gentles, A. J., Newman, A. M., Liu, C. L., et al. (2015). The prognostic landscape of genes and infiltrating immune cells across
human cancers. Nat Med, 21, 938–45. 10.1038/nm.3909
Google Scholar
WorldCat
Crossref
Girardi, M., Oppenheom, D. E., Steele, C. R., et al (2001). Regulation of cutaneous malignancy by gammadelta T cells. Science,
294, 605–9. 10.1126/science.1063916
Google Scholar
WorldCat
Crossref
PubMed
Goodnow, C. C. & Basten, A. (1989). Self-tolerance in B lymphocytes. Semin Immunol, 1, 125–35.
Google Scholar
WorldCat
PubMed
Gross, G. & Eshhar, Z. (2016). Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting
o -tumor toxicities for safe CAR T cell therapy. Annu Rev Pharmacol Toxicol, 56, 59–83. 10.1146/annurev-pharmtox-010814124844
Google Scholar
WorldCat
Crossref
Gubin, M. M., Artyomov, M. N., Mardis, E. R., & Schreiber, R. D. (2015). Tumor neoantigens: building a framework for personalized
cancer immunotherapy. J Clin Invest, 125, 3413–21. 10.1172/JCI80008
Google Scholar
WorldCat
Crossref
Hagerling, C., Casbon, A. J., & Werb, Z. (2015). Balancing the innate immune system in tumor development. Trends Cell Biol, 25,
214–20. 10.1016/j.tcb.2014.11.001
Google Scholar
WorldCat
Crossref
Hammer, G. E. & Ma, A. (2013). Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev
Immunol, 31, 743–91. 10.1146/annurev-immunol-020711-074929
Google Scholar
WorldCat
Crossref
Hanahan, D. & Coussens, L. M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment.
Cancer Cell, 21, 309–22. 10.1016/j.ccr.2012.02.022
Google Scholar
WorldCat
Crossref
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Gabrilovich, D. I., Ostrand-Rosenberg, S., & Bronte, V. (2012). Coordinated regulation of myeloid cells by tumours. Nat Rev
Immunol, 12, 253–68. 10.1038/nri3175
Google Scholar
WorldCat
Crossref
Hanahan, D. & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144, 646–74. 10.1016/j.cell.2011.02.013
Google Scholar
WorldCat
Crossref
PubMed
Hayday, A. & Tigelaar, R. (2003). Immunoregulation by gammadelta cells. Nat Rev Immunol, 3, 233–42. 10.1038/nri1030
Google Scholar
WorldCat
Crossref
Hayday, A. C. (2009). Gammadelta T cells and the lymphoid stress-surveillance response. Immunity, 31, 184–
96. 10.1016/j.immuni.2009.08.006
Google Scholar
WorldCat
Crossref
PubMed
Hori, S., Nomura, T., & Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science,
299, 1057–61. 10.1126/science.1079490
Google Scholar
WorldCat
Crossref
PubMed
Johnson, L. A., Morgan, R. A., Dudley, M. E., et al. (2009). Gene therapy with human and mouse T-cell receptors mediates cancer
regression and targets normal tissues expressing cognate antigen. Blood, 114, 535–46. 10.1182/blood-2009-03-211714
Google Scholar
WorldCat
Crossref
PubMed
Jones, P. T., Dear, P. H., Foote, J., Neuberger, M. S., & Winter, G. (1986). Replacing the complementarity-determining regions in a
human antibody with those from a mouse. Nature, 321, 522–5. 10.1038/321522a0
Google Scholar
WorldCat
Crossref
PubMed
Joyce, J. A. & Fearon, D. T. (2015). T cell exclusion, immune privilege, and the tumor microenvironment. Science, 348, 74–
80. 10.1126/science.aaa6204
Google Scholar
WorldCat
Crossref
Kalos, M. & June, C. H. (2013). Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity, 39,
49–60. 10.1016/j.immuni.2013.07.002
Google Scholar
WorldCat
Crossref
Katsumata, M., Drebin, J. A., & Greene, M. I. (2006). Trastuzumab in breast cancer. N Engl J Med, 354, 640–4; author reply 640–
4. 10.1056/NEJMc053177
Google Scholar
WorldCat
Crossref
Khalil, D. N., Smith, E. L., Brentjens, R. J., & Wolchok, J. D. (2016). The future of cancer treatment: immunomodulation, CARs and
combination immunotherapy. Nat Rev Clin Oncol, 13, 394.
Google Scholar
WorldCat
Kohler, G. & Milstein, C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 256, 495–
7. 10.1038/256495a0
Google Scholar
WorldCat
Crossref
PubMed
Kurosawa, Y. & Tonegawa, S. (1982). Organization, structure, and assembly of immunoglobulin heavy chain diversity DNA
segments. J Exp Med, 155, 201–18. 10.1084/jem.155.1.201
Google Scholar
WorldCat
Crossref
PubMed
Li, B., Li, T., Pignon, J. C., et al. (2016). Landscape of tumor-infiltrating T cell repertoire of human cancers. Nat Genet, 48, 725–
32. 10.1038/ng.3581
Google Scholar
WorldCat
Crossref
Linnemann, C., Mezzadra, R., & Schumacher, T. N. (2014). TCR repertoires of intratumoral T-cell subsets. Immunol Rev, 257, 72–
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Hinrichs, C. S., & Rosenberg, S. A. (2014). Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev,
257, 56–71. 10.1111/imr.12132
Google Scholar
WorldCat
Crossref
82. 10.1111/imr.12140
Google Scholar
WorldCat
Crossref
Mahoney, K. M., Rennert, P. D., & Freeman, G. J. (2015). Combination cancer immunotherapy and new immunomodulatory
targets. Nat Rev Drug Discov, 14, 561–84. 10.1038/nrd4591
Google Scholar
WorldCat
Crossref
Marvel, D. & Gabrilovich, D. I. (2015). Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J
Clin Invest, 125, 3356–64. 10.1172/JCI80005
Google Scholar
WorldCat
Crossref
Mazor, R., Onda, M., & Pastan, I. (2016). Immunogenicity of therapeutic recombinant immunotoxins. Immunol Rev, 270, 152–
64. 10.1111/imr.12390
Google Scholar
WorldCat
Crossref
McGranahan, N., Furness, A. J., Rosenthal, R., et al. (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to
immune checkpoint blockade. Science, 351, 1463–9. 10.1126/science.aaf1490
Google Scholar
WorldCat
Crossref
Medzhitov, R. & Janeway, C. A., Jr. (1997). Innate immunity: impact on the adaptive immune response. Curr Opin Immunol, 9, 4–
9. 10.1016/S0952-7915(97)80152-5
Google Scholar
WorldCat
Crossref
PubMed
Melief, C. J., van Hall, T., Arens, R., Ossendorp, F., & van der Burg, S. H. (2015). Therapeutic cancer vaccines. J Clin Invest, 125,
3401–12. 10.1172/JCI80009
Google Scholar
WorldCat
Crossref
Mellman, I. (2013). Dendritic cells: master regulators of the immune response. Cancer Immunol Res, 1, 145–9. 10.1158/23266066.CIR-13-0102
Google Scholar
WorldCat
Crossref
Mitchell, G. F. & Miller, J. F. (1968). Cell to cell interaction in the immune response. II. The source of hemolysin-forming cells in
irradiated mice given bone marrow and thymus or thoracic duct lymphocytes. J Exp Med, 128, 821–37. 10.1084/jem.128.4.821
Google Scholar
WorldCat
Crossref
PubMed
Mlecnik, B., Bindea, G., Kirilovsky, A., et al. (2016). The tumor microenvironment and Immunoscore are critical determinants of
dissemination to distant metastasis. Sci Transl Med, 8, 327ra326. 10.1126/scitranslmed.aad6352
Google Scholar
WorldCat
Crossref
Molon, B., Ugel, S., Del Pozzo, F., et al. (2011). Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J
Exp Med, 208, 1949–62. 10.1084/jem.20101956
Google Scholar
WorldCat
Crossref
Mueller, D. L. (2010). Mechanisms maintaining peripheral tolerance. Nat Immunol, 11, 21–7. 10.1038/ni.1817
Google Scholar
WorldCat
Crossref
Munoz-Fontela, C., Mandinova, A., Aaronson, S. A., & Lee, S. W. (2016). Emerging roles of p53 and other tumour-suppressor genes
in immune regulation. Nat Rev Immunol, 16, 741–50. 10.1038/nri.2016.99
Google Scholar
WorldCat
Crossref
Obenaus, M., Leitao, C., Leisegang, M., et al. (2015). Identification of human T-cell receptors with optimal a inity to cancer
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Matzinger, P. (1994). Tolerance, danger, and the extended family. Annu Rev Immunol, 12, 991–
1045. 10.1146/annurev.iy.12.040194.005015
Google Scholar
WorldCat
Crossref
PubMed
antigens using antigen-negative humanized mice. Nat Biotechnol, 33, 402–7. 10.1038/nbt.3147
Google Scholar
WorldCat
Crossref
Palucka, K. & Banchereau, J. (2013). Dendritic-cell-based therapeutic cancer vaccines. Immunity, 39, 38–
48. 10.1016/j.immuni.2013.07.004
Google Scholar
WorldCat
Crossref
Park, T. S., Groh, E. M., Patel, K., Kerkar, S. P., Lee, C. C., & Rosenberg, S. A. (2016). Expression of MAGE-A and NY-ESO-1 in primary
and metastatic cancers. J Immunother, 39, 1–7. 10.1097/CJI.0000000000000101
Google Scholar
WorldCat
Crossref
Quail, D. F. & Joyce, J. A. (2013). Microenvironmental regulation of tumor progression and metastasis. Nat Med, 19, 1423–
37. 10.1038/nm.3394
Google Scholar
WorldCat
Crossref
Ramsdell, F. & Ziegler, S. F. (2014). FOXP3 and scurfy: how it all began. Nat Rev Immunol, 14, 343–9. 10.1038/nri3650
Google Scholar
WorldCat
Crossref
Regateiro, F. S., Howie, D., Nolan, K. F., et al. (2011). Generation of anti-inflammatory adenosine by leukocytes is regulated by
TGF-beta. Eur J Immunol, 41, 2955–65. 10.1002/eji.201141512
Google Scholar
WorldCat
Crossref
PubMed
Ribas, A. & Wolchok, J. D (2018). Cancer immunotherapy using checkpoint blockade. Science, 359, 1350–
5. 10.1126/science.aar4060
Google Scholar
WorldCat
Crossref
Richards, D. M., Kyewski, B., & Feuerer, M. (2016). Re-examining the nature and function of self-reactive T cells. Trends Immunol,
37, 114–25. 10.1016/j.it.2015.12.005
Google Scholar
WorldCat
Crossref
Ridge, J. P., Di Rosa, F., & Matzinger, P. (1998). A conditioned dendritic cell can be a temporal bridge between a CD4 + T-helper
and a T-killer cell. Nature, 393, 474–8. 10.1038/30989
Google Scholar
WorldCat
Crossref
PubMed
Riethmuller, G. (2012). Symmetry breaking: bispecific antibodies, the beginnings, and 50 years on. Cancer Immun, 12, 12.
Google Scholar
WorldCat
Rizvi, N. A., Hellmann, M. D., Snyder, A., et al. (2015). Cancer immunology. Mutational landscape determines sensitivity to PD-1
blockade in non-small cell lung cancer. Science, 348, 124–8. 10.1126/science.aaa1348
Google Scholar
WorldCat
Crossref
p. 343
Romagnoli, G. G., Zelante, B. B., Toniolo, P. A., Migliori, I. K., & Barbuto, J. A. (2014). Dendritic cell-derived exosomes may be a tool
for cancer immunotherapy by converting tumor cells into immunogenic targets. Front Immunol, 5, 692.
Google Scholar
WorldCat
Rosenberg, S. A. & Restifo, N. P. (2015). Adoptive cell transfer as personalized immunotherapy for human cancer. Science, 348,
62–8. 10.1126/science.aaa4967
Google Scholar
WorldCat
Crossref
Sato, N., Yamabuki, T., Takano, A., et al. (2010). Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer
Res, 70, 5326–36. 10.1158/0008-5472.CAN-09-3879
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Perro, M., Tsang, J., Xue, S. A., et al. (2010). Generation of multi-functional antigen-specific human T-cells by lentiviral TCR gene
transfer. Gene Ther, 17, 721–32. 10.1038/gt.2010.4
Google Scholar
WorldCat
Crossref
Google Scholar
WorldCat
Crossref
PubMed
Schaefer, L. (2014). Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem, 289,
35237–45. 10.1074/jbc.R114.619304
Google Scholar
WorldCat
Crossref
Schumacher, T. N. & Schreiber, R. D. (2015). Neoantigens in cancer immunotherapy. Science, 348, 69–
74. 10.1126/science.aaa4971
Google Scholar
WorldCat
Crossref
Shimizu, K., Yamasaki, S., Shinga, J., et al. (2016). Systemic DC activation modulates the tumor microenvironment and shapes
the long-lived tumor-specific memory mediated by CD8 + T cells. Cancer Res, 76, 3756–66. 10.1158/0008-5472.CAN-15-3219
Google Scholar
WorldCat
Crossref
Silva-Santos, B., Serre, K., & Norell, H. (2015). Gammadelta T cells in cancer. Nat Rev Immunol, 15, 683–91. 10.1038/nri3904
Google Scholar
WorldCat
Crossref
Simpson, E. (2006). A historical perspective on immunological privilege. Immunol Rev, 213, 12–22. 10.1111/j.1600065X.2006.00434.x
Google Scholar
WorldCat
Crossref
PubMed
Simpson, E. & Nehlsen, S. L. (1971). Prolonged administration of antithymocyte serum in mice. II. Histopathological
investigation. Clin Exp Immunol, 9, 79–98.
Google Scholar
WorldCat
PubMed
Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. (2016). Combination cancer immunotherapies tailored to the tumour
microenvironment. Nat Rev Clin Oncol, 13, 143–58. 10.1038/nrclinonc.2015.209
Google Scholar
WorldCat
Crossref
Staerz, U. D. & Bevan, M. J. (1989). Redirecting the cellular immune response. Int Rev Immunol, 4, 159–
73. 10.3109/08830188909044779
Google Scholar
WorldCat
Crossref
Stein-Streilein, J. & Streilein, J. W. (2002). Anterior chamber associated immune deviation (ACAID): regulation, biological
relevance, and implications for therapy. Int Rev Immunol, 21, 123–52. 10.1080/08830180212066
Google Scholar
WorldCat
Crossref
PubMed
Steinman, R. M., Hawiger, D., & Nussenzweig, M. C. (2003). Tolerogenic dendritic cells. Annu Rev Immunol, 21, 685–
711. 10.1146/annurev.immunol.21.120601.141040
Google Scholar
WorldCat
Crossref
PubMed
Topalian, S. L., Wolchok, J. D., Chan, T. A., et al. (2015). Immunotherapy: The path to win the war on cancer? Cell, 161, 185–
6. 10.1016/j.cell.2015.03.045
Google Scholar
WorldCat
Crossref
van der Burg, S. H., Arens, R., Ossendorp, F., van Hall, T., & Melief, C. J. (2016). Vaccines for established cancer: overcoming the
challenges posed by immune evasion. Nat Rev Cancer, 16, 219–33. 10.1038/nrc.2016.16
Google Scholar
WorldCat
Crossref
Vantourout, P. & Hayday, A. (2013). Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat Rev
Immunol, 13, 88–100. 10.1038/nri3384
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Sharma, P. & Allison, J. P. (2015). Immune checkpoint targeting in cancer therapy: toward combination strategies with curative
potential. Cell, 161, 205–14. 10.1016/j.cell.2015.03.030
Google Scholar
WorldCat
Crossref
Google Scholar
WorldCat
Crossref
Waldmann, H., Howie, D., & Cobbold, S. (2016). Induction of immunological tolerance as a therapeutic procedure. Microbiol
Spectr, 4(4). doi: 10.1128/microbiolspec.MCHD-0019-2015.
Google Scholar
WorldCat
Wang, L., Yi, T., Zhang, W., Pardoll, D. M., & Yu, H. (2010). IL-17 enhances tumor development in carcinogen-induced skin cancer.
Cancer Res, 70, 10112–20. 10.1158/0008-5472.CAN-10-0775
Google Scholar
WorldCat
Crossref
PubMed
Willcox, C. R., Pitard, V., Netzer, S., et al. (2012). Cytomegalovirus and tumor stress surveillance by binding of a human
gammadelta T cell antigen receptor to endothelial protein C receptor. Nat Immunol, 13, 872–9. 10.1038/ni.2394
Google Scholar
WorldCat
Crossref
Woo, S. R., Corrales, L., & Gajewski, T. F. (2015). Innate immune recognition of cancer. Annu Rev Immunol, 33, 445–
74. 10.1146/annurev-immunol-032414-112043
Google Scholar
WorldCat
Crossref
Yamabuki, T., Takano, A., Hayama, S., et al. (2007). Dikkopf-1 as a novel serologic and prognostic biomarker for lung and
esophageal carcinomas. Cancer Res, 67, 2517–25. 10.1158/0008-5472.CAN-06-3369
Google Scholar
WorldCat
Crossref
PubMed
Young, A., Ngiow, S. F., Barkauskas, D. S., et al. (2016). Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor
immune responses. Cancer Cell, 30, 391–403. 10.1016/j.ccell.2016.06.025
Google Scholar
WorldCat
Crossref
Zitvogel, L., Galluzzi, L., Smyth, M. J., & Kroemer, G. (2013). Mechanism of action of conventional and targeted anticancer
therapies: reinstating immunosurveillance. Immunity, 39, 74–88. 10.1016/j.immuni.2013.06.014
Google Scholar
WorldCat
Crossref
© Oxford University Press
Downloaded from https://academic.oup.com/book/24948/chapter/188864572 by guest on 05 November 2023
Ward, J. P., Gubin, M. M., & Schreiber, R. D. (2016). The role of neoantigens in naturally occurring and therapeutically induced
immune responses to cancer. Adv Immunol, 130, 25–74. 10.1016/bs.ai.2016.01.001
Google Scholar
WorldCat
Crossref