Cancer and the immune system
BS963
Elena Klenova, e-mail:
klenovae@essex.ac.uk
Recommended reading
• Immunobiology : the immune system in health and disease
/Charles A. Janeway, Paul Travers, Mark Walport and Mark Shlomchik; 2005,
Garland Science Publishing
• Janeway's immunobiology 7th ed. / Kenneth Murphy, Paul Travers, Mark
Walport ; with contributions by Michael Ehrenstein ... [et al.]; 2009, Garland
Science Publishing
• The Immune system/Peter Parham, 2005, Garland Science Publishing
• Cellular and molecular immunology / Abul K. Abbas, Andrew H. Lichtman,
Shiv Pillai/ 2007, Philadelphia : Saunders Elsevier ( also the 2005 Edition)
• Dunn GP, Koebel CM, Schreiber RD: Interferons, immunity and
cancer immunoediting. Nature Reviews Immunology 2006, 6:836-848.
• Ichim, C.V. Revisiting immunosurveillance and immunostimulation:
Implications for cancer immunotherapy J Transl Med 3, 8 (2005).
• Pardoll D. Does the immune system see tumors as foreign or self? Annu. Rev.
Immunol. 2003, 21:807-39
• Smyth, M. J. et al. A fresh look at tumor immunosurveillance and
immunotherapy. Nature Immunology 2001, 2: 293 – 299.
Plan of the seminar
1. General Introduction ( Cancer and Immune system).
2. Theories of the role of the immune system in cancer.
3. Cells of the immune system involved in anti-tumour
response and basic mechanisms of anti-tumour
immunity.
4. Tumours antigens: novel or over-expressed proteins
produced by tumours that may be recognized by the
immune system.
5. How do tumour cells escape from the immune
system?
6. Anti-tumour therapy. Anti-tumour vaccines.
1. General Introduction ( Cancer
and Immune system).
Cancer
• Uncontrolled growth produces a tumour
( neoplasm).
• Benign - a tumour that is not capable of
indefinite growth. It does not kill the host.
• Malignant - a tumour that grows
indefinitely and often spreads (metastasis).
It can kill the host.
Types of Cancer
(based on the type of affected tissue)
• Carcinoma: Cancer of endo or ectoderm e.g.
Skin or epithelial lining of organs.
• Sarcomas: Cancer of mesoderm e.g. bone.
• Leukemias and Lymphomas: Cancers of
hematopoietic cells
The Immune System
• Innate (non-specific) immune
system (Granulocytes, Macrophages)
– immediately available for combat
• Adaptive (specific) immune system
(T – and B-Lymphocytes)
– Production of antibody (Ab) or cells
specific to combat a particular antigen
Innate and adaptive responses work together
Innate
Adaptive
 Antigen independent
 Immediate (hours)
Antigen-dependent
Slower (days)
 Neutrophils
 NK (Natural Killer) cells
 Macrophages
T cells
B cells
Dendritic cells – a link between the innate and adaptive systems!
Innate immune responses help form adaptive immune
responses, and
Adaptive immune responses utilize the machinery of innate
immunity for effector function
Evidence for the role of immune system in
tumor rejection
• Spontaneous regression
• Regression of metastases after removal of
primary tumor
• Regression after chemotherapy
• Infiltration of tumors by lymphocytes and
macrophages
• Lymphocyte proliferation in draining lymph
nodes
• Higher incidence of cancer after
immunosuppression/immunodeficiency (AIDS,
neonates, aged, transplant patients)
Tumour rejection antigens are specific for
individual tumours
2. Theories of the role of the
immune system in cancer.
Two distinct theories of the role
of the immune system in cancer
• Immunosurveillance - the tumoursuppressing role of the immune system.
• Immunostimulation - the tumourpromoting role of the immune system.
• Tumour and immune system interact:
mutual influence!
Immunosurveillance (immune
surveillance )
• As early as 1909 Paul Ehrlich postulated that
cancer occurs spontaneously in vivo and that the
immune system is able to both recognize and protect
against it .
• In the late 1950s Lewis Thomas introduced the theory
of immunosurveillance, which was subsequently
developed by Sir MacFarlane Burnet .
•The theory states that immunosurveillance is a
physiologic function of the immune system. Cancerous
cells seen as foreign and thus can be constantly
eliminated by immune surveillance.
Ichim, C.V. J Transl Med 3, 8 (2005).
Cancer immunosurveilance: evidence in humans
• Increased incidence of virally-induced tumours in
Immunosuppressed patients
• Studies showing increase in de novo malignant
melanoma in organs transplant patients
• 25-fold increase in incidence of lung
carcinoma in cardiac transplant patients
• Reverse correlations between tumour infiltrating
lymphocytes and tumour survival
Dunn et al. Nature Reviews Immunology 6, 836–848
(2006)
Cancer immunosurveilance: evidence in mice
Dunn et al. Nature Reviews Immunology 6, 836–848 (2006)
Immunostimulation (immune stimulation)
• The proof of the principle that an inappropriate type of
immune response will enhance tumour growth was
demonstrated as early as 1907 by Flexner and Jobling,
who showed that injection of dead autologous tumour
cells enhanced the growth of pre-existing tumours.
•In 1972, Richmond Prehn formulated the theory of
immunostimulation of tumour growth. This theory states
that, in contrast to the strong immune response
generated by transplantable tumours, a quantitatively
mild immune response, such as that generated by
spontaneous tumors, is stimulatory to the growth of
neoplasia.
How the conflicting roles of the immune
response in neoplasia can be explained?
Modern view: The immune system is not a single
entity, but a complex system of constituents. The
concept of immunosurveillance has been modified
and is now considered in three phases:
1. “Elimination phase” - recognition and
destruction of the tumour cells
2. “Equilibrium phase” – occurs if elimination is
not successful. Tumour cells undergo changes in
a process called immunoediting.
3. “Escape phase”- tumour cells evolved enough
to grow unimpeded and form a tumour
3. Cells of the immune system
involved in anti-tumour response
and basic mechanisms of antitumour immunity.
The immune system provides one of the body's main
defenses against cancer.
IFN-g
Natural
IFN-g
When normal cells turn into cancer cells, some of the antigens
on their surface change.
These new or altered antigens flag immune defenders,
including cytotoxic T cells, natural killer cells, and macrophages.
Immune cells are generated during hematopoiesis
Cells of the immune system involved in tumour response
Functions:
Phagocytosis
Antigen presentation to T cells
Phagocytosis of microorganisms and
antigen presentation to T cells
Kill tumor and virus-infected cells
Regulates humoral and
cell-mediated immune responses
T-cell classification
•Classification is based on the Structure & antigen specificity of TCR (T-cell receptor)
•T cells are divided into two major groups: CD4+ T-helper and CD8+ T-cytotoxic cells.
•The differentiation of T cells into CD4 vs. CD8 occurs during their development in the thymus.
T cells: CD 4 & 8 Accessory Molecules
• CD4 + helper T cells (TH); further subdivided into type 1 and type 2, also known as Th1 and Th2. The
differentiation of Th cells into Th1 and Th2 occurs only after these cells have been activated during
an immune response, in the peripheral lymphoid system.
- Only recognize antigen bound to MHC class II molecule
• CD 8 + cytotoxic T cells (TC)
-Only recognize antigen bound to MHC class I molecules
• T cells require two signals for activation:
1 -from TCR /MHC-antigen complex & CD4 or CD8/MHC complex
2-from an accessory molecule CD28
When all appropriate signals are received, T-cells clonally expand as a result of IL-2 secretion forming
a population of T-cells with the same antigen specificity----further differentiation into memory
& effector cells
MHC-Major Histocompatibility Complex: Role of MHC Molecules
• Membrane-bound glycoproteins
- Class I and Class II MHC molecules
- MHC genes highly polymorphic-within each
species there are many
different forms (alleles)
• MHC function as antigen-recognition
molecules
- Can bind to a spectrum of antigenic peptides;
polymorphism allows
for diversity in antigen recognition
• MHC I ---expressed on all nucleated cells
- Present endogenous antigens
-CD 8 + (Tc cells) -recognize antigen on MHC I
• MHC II ---expressed on Antigen presenting
cells (APC)
- Present exogenous antigen
- CD 4 + (Th cells) -recognize antigen on MHC II
Anti-tumour immunity: basic
mechanisms
Immunology 7th Ed
( D. Male et al)
Antigen – presenting cells (APC)
Dendritic Cells (DC)
• DCs are the interface between innate and adaptive
immunity
• DCs are immature as they circulate waiting to
encounter pathogens. At this point, they are highly
phagocytic, but not good stimulators of adaptive T cell
responses
• Once they are activated, they secrete cytokines to
initiate inflammation and then they migrate to lymph
nodes and mature
• As mature DCs they are very efficient APCs for T cell
stimulation
• Other APCs: macrophages, neutrophils, Blymphocytes, monocytes.
Anti-tumour immunity: basic mechanisms
•Presence of tumour cells
and tumour antigens may
initiate the release of
“danger” signals; cytokines,
heat shock proteins (HSP),
uric acid etc.
• Activation and maturation
of dendritic cells, which
present tumour antigens to
CD8 and CD4 cells
• Clonal expansion of CD8 and
CD4 T cells; migration from
the lymph node
• Subsequent T cell mediated
destruction of tumour cells
Smyth, M. J. et al. Nature Immunology 2, 293 - 299 (2001)
The cellular basis of tumour immunology: CTL - tumor cell interactions
Antigen presentation by antigen presenting cells
Natural Killer (NK) Cells
- First identified by having the ability to lytically kill certain
tumor cell lines without prior sensitization
- Kill target cell by release of cytotoxic granules containing
granzymes and perforin which penetrate target cell
membrane and induce programmed cell death
- Can mediate Antibody-Dependent Cellular Cytotoxicity
(ADCC); (mechanism of immunologic lysis in which
cellular targets sensitized by specific antibodies are
efficiently and selectively lysed by nonspecific effectors)
- Kill virally-infected cells with missing MHC class I
- Activated by IFN-a/b or IL-12 (produced rapidly by
activated macrophages)
Fig 8-3
- Activated NK cells secrete IFNg, acts on macrophages to
increase microbial phagocytosis and killing
Basic facts about NK cells
They get easily activated, do not adapt and kill MHC-negative cells.
4. Tumours antigens: novel or over-expressed
proteins produced by tumours that may be
recognized by the immune system.
Antigens expressed on tumour cells
Major Histocompatability Complex antigens
TSTA
Tumour-specific
transplantation Ag
TATA
Tumour-associated
transplantation Ag
TSTA: unique to a tumour
Play an important role in tumor rejection.
TATA: shared by normal and tumour cells
Tumour-associated developmental Ag (TADA)
Tumour-associated viral Ag (TAVA)
Tumor-Associated Developmental
Antigens
• Found on cancer cells and on fetal cells.
• Do not trigger anti-tumor immunity.
• Used in diagnosis.
–Alpha-fetoprotein(AFP)
Cancers of liver
–Carcinoembryonic Ag (CEA)
colorectal cancer
Identification of tumour antigens
• Use the immune system as a tool for
the identification of
immunogenic antigens
• Gene profiling
– genomics or transciptomics
• Proteomic approaches
– peptidomics, serum profiling
• In-silico bioinformatic approaches
– probing EST databases
Other Tumor associated antigens
Shared tumour antigens: common in different tumours
• Cancer-testis antigens
MAGE family etc.
• Differentiation antigens
Melan-A/MART-1, gp100
• Over-expressed proto-oncogenes
HER2/neu, WT1
• Some additional antigens
MUC-1 (over-expressed)
Unique tumour antigens
Point mutations: p53, Raf, Bcr/Abl
• – viral antigens: HPV, EBV etc.
5. How do tumour cells escape
from the immune system?
Malignant cells can be controlled by
immunosurveillance
NK – Natural Killers
CD4, CD8 and gd – types of T-lymphocytes
6. Anti-tumour therapy.
Anti-tumour vaccines.
Ideal tumour antigen:
- displays tumour-specific
expression
- is immunogenic
- plays an important functional role
in cell survival / differentiation /
metastasis etc.
Anti-tumour therapy
 Specific
Active Immunization: Vaccination with viral
Antigens: e.g.
 Hepatitis B virus
Human Papilloma virus (HPV) – success
story.
 Ab Therapy
Abs specific for oncogene product e.g. Abs
against HER2/neu (Herceptin or
trastuzumab)
Nonspecific:
BCG (Bacillus Calmette-Guerin) Mycobacteria
used as an adjuvant - melanoma, bladder
carcinoma
Irradiated tumour cells ( with or without BCG)
Normal
Macro
phage
Activated
Macro
phage
Tumor
Tumor
lysis
 Adoptive immunotherapy
– ex vivo manipulation and transfer of effector cells
- Antibody-Dependent Cellular Cytotoxicity (ADCC)
Gene therapy
Introduce cytokine genes for IL-2, IL-4, IL-12, IFN-g etc into tumor cells to
induce immune response.
IL-2
T cell
tumour
IFN-g
Macrophages