The immune system plays an important role in tumor immunity by recognizing and destroying tumor cells. However, tumors have developed several mechanisms to evade the immune system. Tumors express a variety of tumor antigens that can elicit an immune response, but they often downregulate antigen expression or lose antigenicity over time. Additionally, tumors employ immunosuppressive strategies like increasing immunosuppressive cytokines or reducing co-stimulatory molecules to avoid immune detection and destruction. While immune surveillance exists, tumors have found ways to circumvent it through immune escape mechanisms.

1. TUMOR IMMUNITY

2. TABLE OF CONTENTS
 Introduction
 Tumor antigens
 Antitumor effector mechanisms
 Immune surveillance and immune evasion by
tumors

3. 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.

4. 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

5. ROLE OF IMMUNE SYSTEM
The immune system plays an important role
 in distinguishing self from non self molecules
 Eliminating infectious agents

6. 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.

7. 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

8.  Many tumors elicit an immune response due
to tumor antigens.
 These tumors evade the immune response
through several mechanisms.

9. 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

10. 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

11. 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.g
HER2/NEU oncogene in breat cancer

12. 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

13. 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

14. 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.

15. 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

16. 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

17. 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

18. 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)

19. 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

20. 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

21. 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.

22.  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?

23. 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.

24. 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.

25. 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

26. 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.

27. 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.

28.  References
Robbins basic pathology
Class-notes