TUMOR IMMUNITY

TABLE OF CONTENTS

Introduction

Tumor antigens

Antitumor effector mechanisms

Immune surveillance and immune evasion by

tumors

INTRODUCTION

Tumors arise from accumulated genetic

mutations.

A tumor is formed by clonal expansion of a

single precursor cell that has incurred genetic

damage.

Carcinogenesis is a multistep process at both the

phenotypic and the genetic levels resulting

from accumulation of multiple mutations.

PRINCIPAL TARGETS OF

GENETIC DAMAGE

Types of genes controlling cancer

4 classes of regulatory genes

Growth promoting proto –oncogenes

Growth inhibiting tumor supressor genes

Genes that regulate programmed cell death

Genes involved in DNA repair

ROLE OF IMMUNE SYSTEM

The immune system plays an important role

in distinguishing self from non self molecules

Eliminating infectious agents

IMMMUNE SURVEILLANCE

Lewis Thomas and Macfarlane Burnet

formalized a concept that there is recognition

and destruction of non-self tumor cells by the

immune system.(immunological resistance of

the host against the development of cancer)

this is known as immune surveillance.

EVIDENCE FOR TUMOR

IMMUNITY

Regression of metastases after removal of

primary tumor

Infiltrations of tumors by lymphocytes and

macrophages

Lymphocyte proliferation in draining sites of

cancer

Direct demonstration of tumor specific T-

cells and antibodies in patients

Increased cancer risk after

immunosuppression and immunodeficiency

Many tumors elicit an immune response due

to tumor antigens.

These tumors evade the immune response

through several mechanisms.

CLASSIFICATION OF TUMOR

ANTIGENS

2 categories of tumor antigens are present

based on their pattern of expression

Tumor specific antigens-present only on

tumor cells and not on any normal cells

Tumor associated antigens-present on tumor

cells and also on some normal cells

CLASSIFICATION OF TUMOR

ANTIGEN

Based on their molecular structure and source

1)Products of mutated oncogenes and tumor

suppressor genes

2)Products of the mutated genes

3)Overexpressed or aberrantly expressed cellular

proteins

4)Tumor antigens produced by oncogenic viruses

5)Oncofetal antigens

6)Altered cell surface glycolipids and glycoproteins

PRODUCTS OF ONCOGENES

AND TUMOR SUPPRESSOR

GENES

Due to neoplastic conditions,genetic alterations lead

to expression of cell surface antigens which are not

recognized as self by immune system

Antigens are derived from mutant oncoproteins and

tumor suppressor proteins

Unique tumor antigens arise from beta-

Catenin,RAS,P53 and CDK4

Since mutant genes are present only in tumors,their

peptides are expressed only in tumors

Also unmutated oncogenes are overexpressed e.gHER2/NEU oncogene in breat cancer

PRODUCTS OF OTHER

MUTATED GENES

Lack of genetic stability leads to mutation of genes whose product are not related to the transformed phenotype and have no known function.So products of these mutated genes are potential tumor antigen.

Mutated cellular proteins are found more common in chemical carcinogen or radiation induced animal tumors

It results in an immune response because there is no self-tolerance against them

TUMOR ANTIGENS PRODUCED

BY ONCOGENIC VIRUSES

Oncogenic viruses(eg:HPV,EBV,HBV) produce

proteins that are recognized as foreign by the

immune system

Cytotoxic lymphocytes recognize antigens of

these viruses and plays a role in surveillance

since they can kill virus-induced tumor cells.

E.g vaccines against HPV antigens are effective

in prevention of cervical cancers in females

OVEREXPRESSED OR

ABBERANTLY EXPRESSED

CELLULAR PROTEINS

Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit immune responses

1)Tyrosinase

T cells recognise peptides from tyrosinase but amount of tyrosinase is so few that it fails to induce tolerance in immune system.

2) MAGE(melanoma antigen gene) is expressed on melanomas-

even if it is tumor specific,it is not unique for individual tumors.It is expressed in carcinomas of lung,liver,stomach and esophagus.

ONCOFETAL ANTIGENS

Proteins that are expressed during embryogenesis but not

in normal adult tissues

Their main importance is that they act as markers and aid

in tumor diagnosis

E.g CEA(carcino embryonic antigen)

Normally expressed during fetal life on fetal gut

GIT,pancreas,biliary system and cancer breast

Alpha fetoprotein(AFP);

Normally expressed in fetal life

Hepatocellular carcinoma

ALTERED CELL SURFACE

GLYCOLIPIDS AND

GLYCOPROTEINS

Expression of higher than normal levels and abnormal forms of surface glycoproteins and glycolipids

They serve as diagnostic markers and used for cancer therapy

They include gangliosides,blood group antigens and mucins.

E.gCA-125 – expressed on ovarian carcinomas

CA-19-9 – expressed on carcinoma in pancreas and biliary tract

MUC-1 – expressed on breast carcinomas

CELL TYPE SPECIFIC

DIFFERENTIATION ANTIGENS

Tumors express molecules that are abnormally present on the cells of origin.These antigens are important because they are specific for particular lineages and are called differentiation antigens.

They are targets of immunotherapy and help in identifying tissue of origin of tumors.

E.g B-cell derived lymphoma may be diagnosed as B-cell derived tumors by detection of surface markers characteristic of this lineage such as CD20

ANTITUMOR EFFECTOR

MECHANISM

Cell mediated immunity is dominant anti tumor

mechanism in vivo.The antitumor effector

mechanism occur as follows:

Cytotoxic T lymphocytes

CTLs are the main immune defense mechanism.

They recognize peptides derived from cytoplasmic

proteins that are displayed bound to class 1 MHC

molecules.CTLs play an important role in virus

associated neoplasms(e.g EBV and HPV-induced

tumors)

NATURAL KILLER CELLS

They are capable of destroying tumor cells

without prior sensitization-first line of defence

against tumor cells

After activation of IL-2 and IL-5 NK cells can

lyse a wide range of human tumors

They recognize stress induced antigens and cells

that have incurred DNA damage and are at risk

for neoplastic transformation

Furthermore,T cells and NK cells are competitive

antitumor mechanism.Tumors that fails to express

MHC-class 1 antigen are recognised by NK cells

rather than T cells

MACROPHAGES

Activated macrophages exhibit toxicity against

tumor cells in vitro

They may kill tumors by same mechanisms for

killing of microbes

E.g production of reactive oxygen metabolites or

by secretion of tumor necrosis factor

HUMORAL MECHANISM

There is no evidence for protective effects of

antitumor antibodies against spontaneous

tumor but administration of monoclonnal

antibodies against tumor cells can be

therapeutically effective.

The strongest argument for immune

surveillance is the increased frequency of

cancer in immunocompromised

hosts.Immunosupressed patients have an

increased risk for development of cancer.

If immune surveillance exist,then how do

cancers evade the immune system in

immunocompetent individual?

ESCAPE MECHANISMS

1)Selective outgrowth of antigen negative variants

During tumor progression strongly immunogenic

subclones may be eliminated.

For e.g,in immunocompromised mice,tumors

express the antigens and there is subsequent

elimination of tumor by the immune system

whereas similar tumors arising in

immunocompetent people are not immunogenic.

2)loss or reduced expression of histocompatibility

Tumor cells may fail to express normal levels of

human leucocyte antigen class 1,thus escaping

attacks of CTLs.However,these cells may trigger

NK cells.

3)Immunosupression

Oncogenic agents suppress the host immune responses.

e.g TGF-beta is a strong immunosuppressant

Sometimes immune response induced by tumor may inhibit tumor immunity

E.g recognition of tumor cells may lead to activation of regulatory T-cells that suppress immune responses.

Some tumors express Fas on immune cell surfaces and induce the immune cell to enter apoptosis

4)Antigen masking

Tumor cells produce a thicker coat of external glycocalyx

molecules such as sialic acid containing muccopolysaccharides

than normal cells.

The thick coat blocks access of immune cells to antigen presenting

molecules ,thus preventing antigen recognition and cell killing.

5)Downregulation of co-stimulatory molecules

Co-stimulatory molecules are required to initiate

strong T-cells responses.

Many tumors reduce expression of these co-

stimulatory molecules.

References

Robbins basic pathology

Class-notes