T UMOR IMMUNITY

TABLE OF CONTENTS

 Introduction
 Tumor antigens
 Antitumor effector mechanisms
 Immune surveillance and immune evasion by
tumors
 I NTRODUCTION

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.
 P RINCIPAL 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
 R OLE OF IMMUNE SYSTEM

The immune system plays an important role

 in distinguishing self from non self molecules
 Eliminating infectious agents
 I MMMUNE 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.
 E VIDENCE 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.
 C LASSIFICATION 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
 C LASSIFICATION 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

 P RODUCTS 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.g

HER2/NEU oncogene in breat cancer
 P RODUCTS 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
T UMOR 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
 O VEREXPRESSED 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.
 O NCOFETAL 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
 A LTERED 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
 C ELL 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
 A NTITUMOR 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)
 N ATURAL 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
 M ACROPHAGES

 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
 H UMORAL 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?
 E SCAPE 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