IMMUNE RESPONSE TO TUMORS-Humoral immunity
-Cellular Immunity- Failure of Host Defenses
- Evasion of Immune Responses by Tumors
- Cancer Immunosurveillance vs Immunoediting- Immunotherapy
2. • The immune response to cancer can be viewed as a specialised case of
immunity in which the malignant cell has adapted and learned how to
persist.
• Burnet and Thomas put forth the immunological surveillance theory as the
immune system continually surveyed the body for the presence of
malignant cells, which were continuously arising as a result of mutations.
• Potential strength of immune surveillance is based on the knowledge that
cancer cells express tumour-associated antigens (TAAs) or tumour-specific
antigens (TSAs) that can be recognised by the immune system as foreign
elements.
• Development of cancer can be explained by the ability of tumour cells to
evade immune recognition either by the failure of the immune system or by
the induction of immune tolerance or other inhibitory mechanisms that
allows tumour to escape immune detection and elimination.
3. • The immune response to foreign antigens consists of
▫ Humoral mechanisms (eg, antibodies)
▫ Cellular mechanisms
• Most humoral responses cannot prevent tumor growth.
• Effector cells, such as T cells, macrophages, and NK cells,
have relatively effective tumoricidal abilities.
• Effector cell activity is induced by cells that present tumor-
specific antigens (TSAs) or tumor-associated antigens (TAAs)
on their surface (these cells are called antigen-presenting cells)
and is supported by cytokines (such as interleukins,
interferons).
• Despite the activity of effector cells, host immunoreactivity
may fail to control tumor occurrence and growth.
4. Humoral immunity
• Humoral antibodies do not appear to confer significant protection against
tumor growth. Most antibodies cannot recognize TAAs.
• Humoral antibodies that react with tumor cells in vitro have been detected in
the sera of patients with various tumors, such as Burkitts lymphoma,
melanoma, osteosarcoma, neuroblastoma, lund and breast carcinomas.
• Cytotoxic antibodies are directed against surface antigens of tumor cells.
• These antibodies can exert anti-tumor effects through complement fixation
or by serving as a flag for destruction of tumor cells by T cells (antibody-
dependent cell-mediated cytotoxicity).
• Another population of humoral antibodies, called enhancing antibodies
(blocking antibodies), may actually favor rather than inhibit tumor growth.
5.
6. Cellular Immunity
• The T cell is the primary cell responsible for direct recognition and killing of tumor
cells.
• T cells carry out immunologic surveillance, proliferate and destroy newly
transformed tumor cells after recognizing TAAs. Some cells require the presence of
humoral antibodies directed against the tumor cells (antibody-dependent cellular
cytotoxicity) to kill tumor cells.
• In contrast, suppressor T cells inhibit the immune response against tumors.
Cytotoxic T lymphocytes
• (CTLs) recognize antigens on target cells and lyse these cells.
• These antigens may be cell surface proteins or may be intracellular proteins (eg,
TAAs) that are expressed on the surface in combination with class I major
histocompatibility complex (MHC) molecules.
• Tumor-specific CTLs have been found in Sarcomas, carcinomas(lung, breast,
cervical,colon), malanomas.
7. Natural killer (NK) cells
• NK cells are effector cells with tumoricidal activity.
• NK cells lack the receptor for antigen detection but can
recognize normal cells infected with viruses or tumor
cells.
• Their tumoricidal activity is termed natural because it is
not induced by a specific antigen.
• Evidence suggests that class I MHC molecules on the
surface of normal cells inhibit NK cells and prevent lysis.
• Thus, the decreased level of class I molecule expression
characteristic of many tumor cells may allow activation
of NK cells and subsequent tumor lysis.
8. Macrophages
• Macrophages can kill specific tumor cells when activated by a
combination of factors, including lymphokines (soluble factors
produced by T cells) and interferon.
• They are less effective than T-cell–mediated cytotoxic mechanisms.
Under certain circumstances, macrophages may present TAAs to T
cells and stimulate tumor-specific immune response.
• There are at least 2 classes of tumor-associated macrophages (TAM):
TAM-1 (M1) cells facilitate T cell killing of tumors
TAM-2 (M2) cells promote tumor tolerance
• M1 and M2 are considered to exist on a continuum until they
maximally differentiate (polarize) into M1 and M2. Such polarization
can vary over time and depends on the stage and type of cancer as
well as treatments.
9. Dendritic cells
• Dendritic cells are dedicated antigen-presenting cells present in
barrier tissues (such as skin, lymph nodes). They play a central
role in initiation of tumor-specific immune response.
• These cells take up tumor-associated proteins, process them, and
present TAAs to T cells to stimulate the CTL response against
tumor. Several classes of dendritic cells can mediate tumor
promotion or suppression.
Lymphokines
• Lymphokines produced by immune cells stimulate growth or
induce activities of other immune cells.
• Such lymphokines include interleukin-2 (IL-2), also known as T-
cell growth factor, and the interferons. IL-12 is produced by
dendritic cells and specifically induces CTLs, thereby enhancing
antitumor immune responses.
10. Regulatory T cells
• T reg cells are normally present in the body and help prevent
autoimmune reactions.
• They are produced during the active phase of immune responses
to pathogens and limit the strong immune response that could
damage the host. Accumulation of these cells in cancers inhibits
antitumor immune responses.
Myeloid-derived suppressor cells
• Myeloid-derived suppressor cells consist of immature myeloid
cells and their precursors. These cells increase in number in
cancer, inflammation and infection. The cells have potent immune
suppressive activity.
• Two populations of these cells are recognized:
▫ Granulocytic
▫ Monocytic
• Myeloid-derived suppressor cells accumulate in large numbers in
cancers and predict poor clinical outcomes in various types of
cancer.
11. Role of the Adaptive Immune System in Tumour Immunity: Recognition of TAAs on Tumour Cells by T Cells and Other Cells
12.
13. Failure of Host Defenses
• Although many tumors are eliminated by the immune system, others
continue to grow despite the presence of TAAs. Several mechanisms
have been proposed to explain this deficient host response to the TAA,
including the following:
▫ Specific immunologic tolerance to TAAs in a process that involves APC’s
and suppressor T cells, possibly secondary to prenatal exposure to the antigen
▫ Suppression of immune response by chemical, physical, or viral agents (eg,
helper T-cell destruction by HIV)
▫ Suppression of the immune response by cytotoxic drugs or radiation
▫ Suppression of the immune response by the tumor itself through various
complex and largely uncharacterized mechanisms that cause various
problems including decreased T, B, APC function, decreased IL-2 production,
and increased circulating soluble IL-2 receptors (which bind and hence
inactivate IL-2)
▫ Presence and activity of TAM-2 (M2) polarized cells, promoting tumor
tolerance
14. Evasion of Immune Responses by Tumors
• Many cancers develop mechanisms that allow them to evade anti-
tumor immune responses.
• These mechanisms can broadly be divided into those that are
intrinsic to the tumor cells and those that are mediated by other
cells.
• Understanding the immune evasion mechanisms of tumors, is
important to prevent immune evasion that will increase the
immunogenicity of tumors and maximize the responses of the host.
1. Escaping Immune Recognition by Loss of Antigen Expression
2. Active Inhibition of Immune Responses
15. Escaping Immune Recognition by Loss of Antigen Expression
• Immune responses to tumor cells impart selective pressures that result
in the survival and outgrowth of variant tumor cells with reduced
immunogenicity, by a process called tumor immunoediting.
• Tumors developing in the setting of a normal immune system become
less immunogenic over time, which is consistent with the selection of less
immunogenic variant cells.
• Given the high mitotic rate of tumor cells and their genetic instability,
mutations or deletions in genes encoding tumor antigens are common.
• If these antigens are not required for growth of the tumors or
maintenance of the transformed phenotype, the antigen-negative tumor
cells will have a growth advantage in the face of the host immune system.
16. • Thus, tumor immunoediting is thought to underlie the
emergence of tumors that escape immune surveillance.
• In addition to loss of tumor-specific antigens, class I MHC
expression may be down-regulated on tumor cells so that they
cannot be recognized by CTLs.
• Various tumors show decreased synthesis of class I MHC
molecules, β2-microglobulin, or components of the antigen
processing machinery, including the transporter associated
with antigen processing and some subunits of the proteasome.
• These mechanisms are presumably adaptations of the tumors
that arise in response to the selection pressures of host
immunity, and they may allow tumor cells to evade T cell–
mediated immune responses.
17. Active Inhibition of Immune Responses
• Tumors may engage inhibitory mechanisms that suppress immune responses.
• There is strong experimental and clinical evidence that T cell responses to
some tumors are inhibited by the involvement of CTLA-4 or PD-1, two of
the best-defined inhibitory pathways in T cells.
• Secreted products of tumor cells may suppress antitumor immune responses.
Regulatory T cells may suppress T cell responses to tumors.
• Tumor-associated macrophages may promote tumor growth and
invasiveness by altering the tissue microenvironment and by suppressing T
cell responses.
• Myeloid-derived suppressor cells (MDSCs) are immature myeloid precursors
that are recruited from the bone marrow and accumulate in lymphoid tissues,
blood, or tumors of tumor-bearing animals and cancer patients and suppress
anti-tumor innate and T cell responses.
18. Cancer Immunosurveillance vs Immunoediting
Cancer immunoediting process consists of three phases:
▫ Elimination
▫ Equilibrium
▫ Escape
• Elimination phase corresponds to the concept of cancer
immunosurveillance, whereby nascent tumour cells are
successfully recognised and eliminated by the immune system,
thus returning the tissues to their normal state of function.
• Tumour cells that elude the immunosurveillance phase will
progress to the immune editing phase, called the equilibrium
phase of advanced oncogenesis, where tumour expansion and
metastasis are minimal (tumour dormancy) and usually occur
without symptoms.
19. • In the equilibrium phase, the immune system may eventually
eliminate all tumour cells leading to an outcome similar to the
elimination phase.
• In a second scenario, the constant interaction of the immune
system with tumours over a long period of time may actually
“edit” or sculpt the phenotype of the developing tumour,
resulting in the immunoselection of a tumour that has been
shaped into a less-immunogenic state.
• Tumours that are no longer susceptible to immune attack then
progress into the immunoediting process, termed “escape.”
The emergence of clinical symptoms of cancer generally
correlates with the escape stage.
• Tumour subverts the immune system, either directly through
its nonimmunogenic phenotype, or indirectly through a variety
of immunosuppressive mechanisms.
20.
21. Immunotherapy
• Immunotherapy also called biologic therapy, is a type of
cancer treatment that boosts the body's natural defenses to
fight cancer.
• It uses substances made by the body or in a laboratory to
improve or restore immune system function.
• Immunotherapy may work by:
▫ Stopping or slowing the growth of cancer cells
▫ Stopping cancer from spreading to other parts of the body
▫ Helping the immune system work better at destroying
cancer cells
22. There are several types of immunotherapy,
including:
▫ Monoclonal antibodies and tumor-agnostic
therapies
▫ Non-specific immunotherapies
▫ Oncolytic virus therapy
▫ T-cell therapy
▫ Cancer vaccines
