Tumor Immunology
Cancer
•Cancer remains one of the leading causes of death
globally, with an estimated 12.7 million cases around the
world affecting both sexes equally. This number is
expected to increase to 21 million by 2030.
•Appearance of a tumor (from the Latin word for
“swelling”)
results
from
ABNORMAL
PROLIFERATION of cells, through the loss or
modification of normal growth control.
•Cells which normally do not divide (e.g. muscle or
kidney cells) may start proliferating, or cells which
normally do proliferate (e.g. basal epithelial cells or
hemopoeitic cells) may begin dividing in an uncontrolled
fashion.
Carcinogens
•Radiation: Ultraviolet light, sunshine; X-rays,
radioactive elements induce DNA damage and
chromosome breaks.
•Chemical: smoke and tar, countless chemicals that
damage DNA (mutagens).
•Oncogenic viruses: insert DNA or cDNA copies of viral
oncogens into the genome of host target cells.
• Hereditary: certain oncogenes are inheritable.
Classification of cancer
•Carcinomas: epithelial origin involving the skin,
mucous membranes, epithelial cells in glands
•Sarcomas: cancer of connective tissue.
•Lymphomas: T- B-cell, Hodgkin’s, Burkitt’s lymhomas;
- solid tumors
•Leukemias: disseminated tumors - may be lymphoid,
myeloid, acute and chronic.
Tumor Immunology
•Tumor antigens
•Effectors mechanisms in anti-tumor immunity
•Mechanisms of tumor evasion of the Immune system
•Immunotherapy for tumors
Tumor Antigen
•Many tumors can be shown to express cell
surface antigens which are not expressed in the
normal progenitor cells before the neoplastic
transformation event.
•These antigens have been categorized based on
their nature and distribution, resulting in a
complex collection of acronyms, some of which
are defined as:
Tumor Antigen
1. Tumor-Specific Transplantation Antigens, or TSTA
Chemical or radiation-induced tumors each generally
express a unique neo-antigen, different from other
tumors induced by the same or different agent.
2. Tumor-Associated Transplantation Antigens, or
TATA
Tumors induced by the same virus express antigens
shared between different tumors. These consist of
membrane-expressed virally encoded antigens, and have
been termed Tumor-Associated Transplantation Antigens
(since they are not, strictly speaking, tumor “specific”).
Tumor Antigen
3. Oncofetal antigens:
•These are TATAs which are more or less selectively
expressed on tumors, but are also shared with some
normal fetal or embryonic tissues.
•Examples include carcinoembryonic antigen (CEA,
shared with healthy fetal gut tissue), and alphafetoprotein (AFP, also present in the serum of healthy
infants, but decreasing by one year of age).
Tumors stimulate an immune response
•Animals can be immunized against tumors
•Immunity is transferable from immune to naïve animals
•Tumor specific antibodies and cell have been detected in
humans with some malignancies
carcinogen
results in mutation
proto-oncogenes
increased GF
increased GF receptors
oncogenes
exaggerated response to GF
tumor
suppressor
genes
inherited
defect
dysfunctional
tumor suppressor
genes
loss of ability to
repair damaged
cells or induce
apoptosis
Four mechanisms of oncogene activity to deregulate cell division
⦿ Escape
normal intercellular communication
⦿ Allow for rapid growth
⦿ Increased mobility of cells
⦿ Invade tissues
⦿ Metastasis
⦿ Evade the immune system
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EXPERIMENTAL EVIDENCE FOR TUMOR ANTIGENS AND IMMUNE
RESPONSE
Immunosurveillance
•An hypothesis that states that a physiologic function of
the immune system is to recognize and destroy
malignantly transformed cells before they grow into
tumors.
•Implies that cells of the immune system recognize
something “foreign” on transformed/tumor cells.
Immune Surveillance of Tumors
Normal cell
Mutation or virus
Transformed (cancerous) but also antigenic
Immune
response
Dead
Mutation
Transformed (cancerous) but
escapes from immune response
Analogous to a bacterial population being treated with antibiotics
such that antibiotics resistant mutants take over the population
⦿Macrophage/Dendritic
cell attack or
antigen presentation
⦿CD8
cell-mediated cytotoxicity
⦿Antibody
dependent cell mediated
cytotoxicity (ADCC)
⦿Natural
killer cells
Tumors can both activate and suppress
immunity
Tumors can activate the immune response
(ex. expression of foreign antigen with MHCI)
or
suppress the immune response
(activation of T regulatory cells that release IL-10
and TGF) –
the balance determines whether the cancer
becomes clinically relevant or not.
Basic Tumor Immunosurveillance
1) The presence of tumor cells and tumor antigens
initiates the release of “danger” cytokines such as
IFN and heat shock proteins (HSP).
2) These cause the activation and maturation of
dendritic cells such that they present tumor antigens
to CD8 and CD4 cells
3) subsequent T cytotoxic destruction of the tumor
cells occurs
Helper T cells
CD4+ T cells: reacting to class II MHC peptide
complex, they secret cytokines.
cytotoxic T cell response (Th1 helper T cells)
antibody response (Th2 helper T cells)
Dendritic Cells
The professional antigen-presenting cells In the final
common pathway for activating naïveTcells.
Tumor cell
or tumor
derived
antigen
Dendritic and Macrophage
Presentation of Tumor
Antigen to CD4 Cells
A
MMAC
C
MHC II
IL-1
T
helper
Memor
y cell
T
helper
effector
cell
Interferon
T
helper
cell
IL-2
Macrophages and dendritic cells
can directly attack tumor cells,
or more commonly can express
exogenous antigens (TSA’s or
bits of killed tumor cells) to
CD4 cells
Cytotoxic T cells (CTLs)T cells(CTLs)
CD8+ T cells: attaching to class I MHC peptide
complex, they destroy cancer cells by perforating
the membrane with enzymes or by triggering an
apoptotic pathway.
Perforins, apoptotic signals
T
Cytotoxic
Cell Activity
in Tumor
Surveillance
MAC or
B cell
(APC)
MHC 1
T
cytotoxic
cell
T
cytotoxi
c
memory
cells
T
cytotoxic
effector
cells
Exogenous
antigen
Cancer
Cell
T
cytotoxic
cell
Endogenous
antigen
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Cytokines
•Regulating the innate immune system: NK cells, macrophages
and neutrophils; and the adaptive immune system: T and B cells
•IFN- α-- upregulating MHC class I tumor antigens and adhesion
molecules; promoting activity of B and T cells, macrophages, and
dendritic cells.
•IL-2-- T cell growth factor that binds to a specific tripartite
receptor on T cells.
•IL- 12– promoting NK and T cell activity and a growth factor
for B cells
•GM-CSF(Granulocyte-monocyte colony stimuating factor) -reconstituting antigen-presenting cells
Antibody - produced by B cells
•Direct attack: blocking growth factor receptors, arresting
proliferation of tumor cells, or inducing apoptosis.
-- is not usually sufficient to completely protect the body.
• Indirect attack: -- major protective efforts
(1) ADCC(antibody-dependent cell mediated cytotoxicity)
-- recruiting cells that have cytotoxicity, such as monocytes and
macrophages.
(2) CDC (complement dependent cytotoxicity)
-- binding to receptor, initiating the complement system,
'complement cascade’, resulting in a membrane attack
complex causing cell lysis and death.
Do not recognize tumor cell via antigen specific
cell surface receptor, but rather through
receptors that recognize loss of expression of
MHC I molecules, therefore detect “missing
self” common in cancer.
NK
Perforin and enzymes
killer activating receptor
Target cell (infected or
cancerous)
⦿Low
immunogenicity
⦿Antigen
modulation
⦿Immune
suppression by tumor cells or T
regulatory cells
⦿Induction
of lymphocyte apoptosis
Defects in mechanisms of MHCI
production can render cancer cells
“invisible” to CD8 cells
Tumors can escape immunity (and immunotherapy) by selecting for resistant clones
that have occurred due to genetic instability
Elimination refers to
effective immune
surveillance for clones
that express TSA
Equilibrium
refers to the
selection for
resistant
clones (red)
Escape refers to the
rapid proliferation of
resistant clones in the
immunocompetent
host
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Avoidance of tumor surveillance through release of immune
suppressants
1
2
Tumor cells induce apoptosis in T lymphocytes via FAS activation
1) Cancer cells express FAS ligand.
2) Bind to FAS receptor on T lymphocytes leading
to apoptosis.
Cancer Immunotherapy
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•
•
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Immunotherapy is the most recent advanced
technique in cancer therapy.
Cancer Immunotherapy is the use of immune system
to reject Cancer. The main purpose of this premise is
stimulating the patient’s immune system to attack the
malignant tumour cells that are responsible for the
disease.
Immunotherapy works to harness the innate powers of
the immune system to fight cancer.
It fights cancer more powerfully, to offer long-term
protection, with less side effects.
It may hold greater potential than current treatments,
due to unique properties of Immune System.
History
•Although cancer immunotherapy is being touted as a recent
breakthrough in cancer treatment, its origins at Memorial Sloan
Kettering go back more than a century. In the 1890s, William
Coley, a surgeon at New York Cancer Hospital (the predecessor to
Memorial Sloan Kettering) discovered cancer patients who suffered
from infections after surgery often fared better than those who did
not. His finding led to the development of Coley’s toxins, a cocktail
of inactive bacteria injected into tumors that occasionally resulted in
complete remission. But eventually the use of this treatment fell out
of favor.
•In the 1960s, research by Memorial Sloan
Kettering investigator Lloyd Old led to the
discovery of antibody receptors on the surface of
cancer cells, which enabled the development of the
first cancer vaccines and led to the understanding
of how certain white blood cells, known as T cells
or T lymphocytes, can be trained to recognize
cancer.
Monoclonal Antibodies
Cytokines
Adoptive cell Therapy
Cancer Vaccines
Monoclonal Antibodies
•Monoclonal antibody(mAbs) therapy, is most widely used, and a
form of Passive Immunotherapy.
•It is a targeted therapy, directed to a single target on a cancer
cell, usually an antigen or a receptor site on the cancer cell.
•It binds to Cancer cell-surface specific antigens . When it
recognize the antigen against which it is directed, they fit together
like two pieces of a puzzle, setting of a cascade of events leading
to tumour cell death.
Examples: Avastin, Erbitux, Rituxan, Herceptin, Campath,
Zevalin, Bexxar etc.
Naked mAbs
Naked mAbs work alone, and
are referred to as "naked"
because they are unmodified.
⦿ Mark targets for immune
system - bind to targets and
make them more visible. The
immune system is triggered
and then destroys the target.
⦿ Attach to antigens that are
responsible for sending
important signals that
contribute to the target's
reproduction.
⦿ Binding to cell receptors, so
that proteins that trigger
growth are blocked. Usually
used in cancer treatments.
⦿
⦿
Conjugated mAbs
Conjugated mAbs are modified
with additional material.
Radio immunotherapy (RIT) These mAbs have radioactive
particles directly attached, and
deliver them directly to
cancerous cells to kill them.
Chemolabeled - These mAbs
have a chemotherapy drug
attached to their structures,
which would normally be too
powerful if delivered by itself.
This drug kills the cancerous
cell.
Cytokines [Active Immunotherapy]
•Cytokines are a large group of proteins, that function as
short range mediators involved in essentially all
biological processes.
•Cytokines serve as molecular messengers between
cells.
•They have important rate-limiting signals.
•These are chemically made by some immune system
cells.
•They are injected, either under the skin, into a muscle,
or into a vein.
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Interleukins
They act as chemical signals between
white blood cells.
Interlukin-2(IL-2) help immune
system cells grow and divide more
quickly.
A man-made version of IL-2 is
approved to treat advanced kidney
cancer and metastatic melanoma.
IL-2 can be used as a single
treatment for cancer, or can be
combined with chemotherapy or with
other cytokines such as Interferon-α
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Interferons
These interferon (IFN) are
chemicals, helping body to resist
virus infection and cancer.
Types of (IFN) are:
1. IFN-α, 2. IFN-β, 3. IFN-γ
Only INF- α is used to treat cancer.
It is used to treat these cancers:
Hairy cell leukemia, Chronic
myeloid leukemia, Follicular nonhodgkin’s lymphoma, cutaneous tcell lymphoma, kidney cancer,
melanoma, kaposi Sarcoma.
Adoptive Cell Therapy
•Adoptive cell transfer (ACT) is the transfer of cells into a
patient; as a form of cancer immunotherapy.
•It requires the generation of tumour-antigen-reactive-T cells.
•The cells are most commonly derived from the immune
system, with the goal of transferring improved immune
functionality and characteristics along with the cells back to
the patient.
•Interleukin-2 is normally added to the extracted T cells to
boost their effectiveness, but in high doses it can have a toxic
effect.
•The reduced number of injected T cells is accompanied by
reduced IL-2, thereby reducing side effects.
Limitations of Adoptive Cell Therapy
1.
Not all tumour infiltrating lymphocytes grow well enough in
culture to generate the quantity of cells that would be required to
produce a useful anti-tumour effect when they are infused into
the patient.
2.
Not all tumour infiltrating lymphocytes can be made, in culture,
to become more adept at killing the tumour upon return to the
patient.
3.
Autologous therapy is cumbersome and does not easily lend
itself to the commercial scale mass production techniques
necessary to reach the multitude of cancer patients world-wide.
⦿ Unlike
other vaccines,
which defends the
immune system from
germs, Cancer
vaccines make
person’s immune
system attack cancer
cells.
1. Preventive Vaccines:
which are intended to prevent cancer from developing in healthy
people.
2. Treatment Vaccines:
which are intended to treat an existing cancer by strengthening
the body’s natural defence against the cancer.
Cancer preventive vaccines target infectious agent that cause or
contribute to the development of cancer.
Limitations of Cancer Vaccines
1.
2.
3.
4.
5.
Today, most cancer vaccines are targeted: that means it made
against a specific tumour cell antigenic target. The limitations
of targeted vaccines are very similar to the limitations of other
targeted change, the target vaccine becomes ineffective.
Not all antigen are same
Autologous vaccine therapy presents many manufacturing
challenges.
Autologous therapy is costly
Many cancer vaccines are poorly immunogenic and require
the use of adjuvants to elicit an effective immune response.
The addition of adjuvants may increase immunogenicity of
vaccine, but may also increase toxicity.
1.
2.
Many mAbs are not administered as first-line therapy:
mAbs are usually administered as a second, third, or last
resort cancer treatment when the immune system is already
weakened by chemotherapy, surgery and radiation. This may
limit their effectiveness.
Not all antigens are the same:
All cancers may "look" the same, but they are not. Not all
patients' cancers may express the antigen against which a
specific monoclonal antibody is targeted. In general,
response rates to these "targeted therapies" appear to be
around 20 to 30 percent. To optimize this type of therapy, it
will be necessary to identify each subgroup of patients with a
specific cancer and develop therapies targeted to, or directed
specifically at, their individual cancers.
3.
4.
Tumour cells mutate:
as a result of chemotherapy and radiation
treatment, and therefore the target antigen on
the tumour cell at which the therapy is aimed
also can be changed. If the target changes, then
the mAbs, which target those specific antigens,
could become ineffective.
Toxicity:
associated with some targeted therapies can be
significant.
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