2009 Immunity to Tumors

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Immunity to Tumors

Prof. Dr. dr. Djoni Djunaedi, Sp.PD.-KPTI, FINASIM


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General Features of Tumor Immunity

Tumor express antigens that are recognized as

foreign by the immune system of the tumor-

bearing host

Immune responses frequently fail to prevent

the growth of tumors

The immune system can be activated by

external stimuli to effectively kill tumor cells

and eradicate tumors


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Tumor Antigens

Products of Mutated Genes:

Some tumor antigens are produced by oncogenic mutantsof normal cellular genes

Tumor antigens may be produced by randomly mutatedgenes whose products are not related to the transformed

phenotype

Abnormally expressed Cellular Proteins:

Tumor antigens may be normal cellular proteins that areabnormally expressed in tumor cells and elicit immune

responses

Cancer/testis antigens are proteins expressed in gametesand trophoblasts, and in many types of cancers, but not innormal somatic tissues


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Tumor Antigens

Antigens of Oncogenic Viruses:

The products of oncogenic viruses function as

tumor antigens and elicit specific T cell responses

that may serve to eradicate the tumors

Oncofetal Antigens: Oncofetal antigens are proteins that are expressed

at high levels in cancer cells and in normal

developing fetal but not in adult tissues


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Tumor Antigens

Altered Glycolipid and Glycoprotein Antigens: Most human and experimental tumors express higher

than normal levels or abnormal forms of surface

glycoproteins and glycolipids, which may be diagnostic

markers and targets for therapy

Tissue-Specific Differentiation Antigens:

Tumors express molecules that are normally present

on the cells of origin


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Identification

of Tumor

Antigens

Recognized byT

Lymphocytes


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Immune Responses to Tumors

Innate immune responses to Tumors: NK Cells

Macrophages

Adaptive immune responses to Tumors: T Lymphocytes

The principal mechanism of tumor immunity is killing of

tumor cells by CD8+CTLs

CD8+ T cell responses specific for tumor antigens mayrequire cross-presentation of the tumor antigens by

professional APCs, such as dendritic cells

Antibodies


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Evasion of Immune Responses by Tumors

Tumor antigens may induce specific immunologicaltolerance

Regulatory T cells may suppress T cell responses totumors

Tumors lose expression of antigens that elicitimmune responses

Tumors may fail to induce CTLs because most

tumor cells do not express costimulators or class IIMHC molecules

The products of tumor cells may suppress anti-tumor immune responses


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Immunotherapy for Tumors

Stimulation of Active Host Immune Responses toTumors:

Vaccination with Tumor Cells and Tumor Antigens

Augmentation of Host Immunity to Tumors withCostimulators and Cytokines

Blocking Inhibitory Pathways to Promote Tumor Immunity

Nonspecific Stimulation of the Immune System

Passive Immunotherapy for Tumors with T Cells and

Antibodies: Adoptive Cellular Therapy

Graft-versus-Leukemia Effect

Therapy with Anti-tumor Antibodies


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Summary

Tumors express antigens that are recognized by theimmune system, but most tumors are weakly

immunogenic, and immune responses often fail to

prevent the growth of tumors. The immune system

can be stimulated to effectively kill tumors.

Tumor antigens recognized by CTLs are the principal

inducers of and targets for antitumor immunity.

These antigens include mutants of oncogenes andother cellular proteins, normal proteins whose

expression is dysregulated or increased in tumors,

and products of oncogenic viruses.


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Summary

Antibodies specific for tumor cells recognizeantigens that are used for diagnosis and are

potential targets for antibody therapy. These

antigens include oncofetal antigens, which are

expressed normally during fetal life and whoseexpression is dysregulated in some tumors; altered

surface glycoproteins and glycolipids; and molecules

that are normally expressed on the cells from whichthe tumors arise and are thus differentiation

antigens for particular cell types.


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Summary

Immune responses that are capable of killing tumorcells consist of CTLs, NK Cells, and activated

macrophages. The role of these immune effector

mechanisms in protecting individuals from tumors is

not well defined.

Tumors evade immune responses by several

mechanisms, including down-regulating the

expression of MHC molecules, selecting cells that donot express tumor antigens, producing

immunosuppressive substances, and inducing

tolerance to tumor antigens.


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Summary

Immunotherapy for tumor is designed to augmentactive immune responses against these tumors or to

administer tumor-specific immune effectors to

patients.

Immune responses may be actively enhanced by

vaccination with tumor cells or antigens,

administration of tumors modified to express high

levels of costimulators or cytokines that stimulate Tcell proliferation and differentiation, and systemic

administration of cytokines.


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Summary

Anti-tumor immunity may also be enhanced byblocking inhibitory pathways of immunoregulation.

Approaches for passive immunotherapy include:

the administration of anti-tumor antibodies,

antibodies conjugated with toxic drugs (immunotoxins),

and tumor-reactive T cells, and

NK cells isolated from patients and expanded by culture

with growth factors.


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15thDec 2009, Lorne Beach, Melbourne, Australia

Until Next Time

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2009 Immunity to Tumors

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