Tumor Immunopathology

Department of Pathology Gadjah Mada University School of Medicine

Host Defence Against Tumor

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Host Defence Against Tumor

Tumor Immunopathology

Paul Ehrlich tumors are not entirely self antigen, and may be recognized by the immune system immune recognition of autologous tumor cells may be a positive mechanism capable of eliminating tumors

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Host Defence Against Tumor

Tumor Immunopathology

Lewis Thomas & Macfarlane Burnet coined the concept on the term immunosurveillance normal function of the immune system is to survey the body for emerging malignant cells and destroy them

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Host Defence Against Tumor Tumor Immunopathology

The concept of of immunololgy immunololgy of The concept oftumor tumor

Host Defence Against Tumor

Many cancers occur in immunodeficient individuals Cancers may occur in immunocompetent individuals the immune system is not perfect, cannot control the rapidly growing tumors
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Host Defence Against Tumor

Tumor Immunopathology The concept of immunololgy of tumor

Lymphocytic infiltrates occur arround tumors Concept: tumor immunosurveillance not only has the protective role of the immune system in tumor development, but also the effect of the immune system in selecting for tumor variants
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TUMOR IMMUNITY
Normal cell
Genetic alteration

Neoplastic transformation
Expression of surface antigens Non-self antigen Induce tumor surveillance
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TUMOR IMMUNITY

Questions:
1. 2. 3. 4. What is the nature of tumor antigens What host effector systems may recognize tumor cells Is antitumor immunity effective against spontaneous neoplasms Can immune reactions against tumors be exploited for immunotherapy

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Tumor antigen
Tumor antigenicity is usually assessed by: The ability of an animal to resist a live tumor implant after previous immunization with live or killed tumor cells The ability of tumor free host animals to resist challenge when infused with sensitized T cells from a tumor-immunized syngeneic donor The demonstration in vitro of tumor cells destruction by cytotoxic CD8+ T cells derived from a tumor-immunized animal
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Immunogenicity of Tumors

The transplanted tumor is rejected because of immunity acquired as a result of the first tumor transplant.

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Tumor antigen
Two broad categories:

TSA (Tumor Spesific Antigen) TAA (Tissue Associated Antigen)

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Tumor antigen
TSAs (Tumor Specific Antigens) Present only on tumor cells not on any normal counterpart cells Derived from peptides that are uniquely present within tumor cells and presented on the cell surface by class I MHC molecules evoke a cytotoxic cell response TAAs (Tissue Associated Antigens) Present on tumor cells as well as on some normal counterpart cells

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Tumor antigen
TSA (Tumor Spesific Antigen) A. Tissue-specific shared antigen B. Antigen resulting from mutation C. Viral antigen D. Other TAA (Tissue Associated Antigen) A. Tissue specific antigen B. Overexpressed antigen C. Oncofetal antigen D. Differentiation antigen
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A.Tissue-specific shared antigen

Tumor Specific Antigens

Encoded by genes that are silent in virtually all normal adult tissues - but expressed in a number of tumors of various histologic types - Testis (no HLA): the only normal organ in which MAGE protein are present cannot be expressed on their cell surface
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B. Antigen resulting from mutation

Tumor Specific Antigens

Mutated protooncogene and tumor supressor gene P53, K-ras, CDK4, bcr-c-abl
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C. Viral antigens

Tumor Specific Antigens

Antigens derived from oncogenic viruses E7 protein of HPV-16

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D. Other Tumor Antigen

Mucins
May give rise to tumor specific antigen: cancers derived from pancreas, ovary, breast In the normal counterpart cells they (the epitopes) are masked by carbohydrate Glycosylation of mucins generate epitopes For practical purposes these antigens are TSA They are belong to MUC-1

Tumor Specific Antigens

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A. Tissue specific antigen

Tissue Associated Antigen

Shared by tumor cells and their normal untransformed counterparts Melanocytes and melanoma cells both express tyrosinase Includes: MART-1, gp100, tyrosinase
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Tissue Associated Antigens

B. Overexpressed antigen

C-erbB2 (neu): overexpressed in 30% of breast and ovarian cancer

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C. Oncofetal antigens
Normally expressed in embryonic tissue AFP: Alpha Fetoprotein CEA: Carcinoembryonic antigen

Tissue Associated Antigens

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D. Differentiation antigen
Peculiar to the differentiation state at which cancer cells are arrested CD10 (CALLA expressed by early B cell, B-cell lymphoma and leukemia) PSA (Prostate Specific Antigen) -hCG, expressed by syncitial trophoblast
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Tissue Associated antigens

Tumor antigens recognized by CD8+ T cells

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Cellular effectors that mediate immunity

Cytotoxic T lymphocytes Protective role against virus-associated tumors EBV, HPV (possessing MHC class 1) Natural killer cells (NK cells) Lymphocytes capable of destroying tumor cells without prior sensitization (after activation with IL-2), including many that appear non-immunogenic for T cells Macrophages ADCC

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Antitumor Effector Mechanisms

ADCC

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Inflammatory reaction is correlated with better prognosis

In some tumors
Medullary carcinoma of the breast Seminoma NPC

In general no clear correlation exist

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IMMUNOSURVEILLANCE
Facts: Increased occurrence of tumors In immunodeficient host

Immunosurveillance
(it is not perfect)

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Mechanisms to escape from Tumor Immunosurveillance

1. 2. 3. 4. Selective outgrowth of antigen-negative variants Loss or reduced expression of histocompatibility antigens (MHC I) Lack of co-stimulation (CD80, CD86) CD28 Immunosuppression - oncogenic agent : ionizing radiation, chemicals - tumor product : TGF- - immune response induced by tumor cells activation of suppressor T cells Antigen masking (glycocalix molecules) Apoptosis of cytotoxic T cells
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5. 6.
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Mechanisms by which tumors evade the immune system

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