Tumor immunity

Dr. Aye Aye Tun

Lecturer

Pathology Unit

Aimst University

Explain how the immune system of the

host responds to the presence of a

tumour

Learning objectives:

This lecture provides an

understanding of

Tumor antigens

Antitumor effector mechanism

Immunosurveillance

Learning outcomes

At the end of this lecture student will be able to

Prove the role of immunity in cancers

List tumor antigens and specify their importance

Describe the Immunosurveillance of cancer

Explain how the immune system of the host responds to the presence of a tumour

Explain the mechanisms by which tumors evade the immune system

Tumors arise from accumulated

genetic mutations

Carcinogenesis is a multistep process at

both the phenotypic and the genetic

levels

resulting from the accumulation of

multiple mutations

Nonlethal genetic damage lies at the

heart of carcinogenesis

A tumor is formed by the clonal

expansion of a single precursor cell

that has incurred genetic damage

(i.e., tumors are monoclonal)

Types of genes that control cancer

Four classes of regulatory genes

1. growth-promoting proto-oncogenes

2. growth-inhibiting tumor suppressor

genes

3. genes that regulate programmed cell

death (apoptosis)

4. genes involved in DNA repair

principal targets of genetic damage

The immune system play a

critical role in distinguishing self from nonself

molecules

Eliminating infectious agents

Immune system react to

antigens that it recognizes

as foreign

Tumor cells can be recognized by

the immune system as non-self

Paul Ehrlich proposed that

immune-mediated recognition of

autologous tumor cells can be

capable of eliminating

transformed cells

Immune surveillance Lewis Thomas and Macfarlane Burnet

Recognition and destruction of

non-self tumor cells by the

immune system

(immunological resistance of the host

against the development of cancer)

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

Evidence for tumor immunity

Cancer immunoediting describe

the effects of the immune

system in preventing tumor formation

in “sculpting” the immunogenic

properties of tumors to select tumor

cells that escape immune elimination

How does the immune system eliminate

cancer cells?

How do cancer cells escape from

Immunosurveilance?

How can we help to win the battle

between immune system and cancers?

Many tumors do elicit an immune

response due to tumor antigens

Many tumors evade host immune

response through several

mechanisms

two categories

based on their patterns 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 antigens

Classification of tumor antigens

based on their molecular structure and source

1. Products of Mutated Oncogenes and Tumor Suppressor Genes

2. Products of other Mutated Genes

3. Over expressed or Aberrantly Expressed Cellular Proteins

4. Tumor Antigens Produced by Oncogenic Viruses

5. Oncofetal antigens

6. Altered glycolipids and glycoproteins

7. Cell type-specific differentiation antigens

TUMOR ANTIGENS

Products of mutated genesderived from the products of mutant proto-

oncogenes, tumor suppressor genes, or other mutated genes

synthesized in the cytoplasm of tumor cells, and like any cytoplasmic protein, they may enter the class I MHC antigenprocessing pathway and be recognized by CD8+ T cells

In addition, these proteins may enter the class II antigen-processing pathway in antigen-presenting cells that have phagocytosed dead tumor cells, and thus be recognized by CD4+ T cells also

TUMOR ANTIGENS

Products of mutated

genesproducts of β-catenin, RAS, p53,

and CDK4 genes BCR-ABL proteinBecause the mutant proteins are present

only in tumors, their peptides are

expressed only in tumor cells

TUMOR ANTIGENS

Overexpressed or aberrantly

expressed proteins

Tumor antigens may be normal cellular

proteins that are abnormally expressed

in tumor cells and elicit immune

responses

Tyrosinase , MAGE(melanoma antigen gene )

is expressed on melanomas

TUMOR ANTIGENS

Oncofetal antigens

proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues

their main importance is that they provide markers that aid in tumor diagnosis

TUMOR ANTIGENS

Oncofetal antigensCarcino-embryonic antigens (CEA)Carcino-embryonic antigens (CEA)

- - Normally expressed during fetal life on fetal gut

- GIT, pancreas, biliary system and cancer breast

Alpha fetoprotein(AFP):

- - Normally expressed in fetal life

- hepatocellularcarcinoma

TUMOR ANTIGENS

antigens produced by oncogenic

viruses

Oncogenic viruses (eg; HPV,EBV, HBV)

produce proteins that are

recognized as foreign by the

immune system

TUMOR ANTIGENS

Altered Cell Surface Glycolipids and Glycoproteins

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

diagnostic markers and targets for therapy

These altered molecules include gangliosides, blood group antigens, and mucins

TUMOR ANTIGENS

Altered Cell Surface Glycolipids and Glycoproteins

These include

CA-125 - expressed on ovarian carcinomas

CA-19-9- expressed on carcinoma in pancreas & biliary tract

MUC-1 - expressed on breast carcinomas

TUMOR ANTIGENS

Cell Type-Specific Differentiation Antigens

Tumors express molecules that are normally present on the cells of origin

Important for identifying the tissue of origin of tumors

These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types

TUMOR ANTIGENS

Altered Cell Surface Glycolipids and Glycoproteins

Mucins are high-molecular-weight glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide

Tumors often have dysregulated expression of the enzymes that synthesize these carbohydrate side chains, which leads to the appearance of tumor-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core

TUMOR ANTIGENS

Altered Cell Surface Glycolipids and Glycoproteins

These include

CA-125 - expressed on ovarian carcinomas

CA-19-9- expressed on carcinoma in pancreas & biliary tract

MUC-1 - expressed on breast carcinomas

TUMOR ANTIGENS

Cell Type-Specific Differentiation Antigens

typically normal self-antigens, and therefore they do not induce immune responses in tumor-bearing hosts

For example, lymphomas may be diagnosed as B-cell-derived tumors by the detection of surface markers characteristic of this lineage, such as CD10 and CD20

TUMOR ANTIGENS

TUMOR ANTIGENS

Host Response to Tumors

Cellular Immunity

CTL (Cytotoxic T-lymphoctyes)

NK cells

Macrophages

Humoral Immunity

Antibody production by the host against host tumor cells or their constituents for tumor antigens

Host Response to Tumors

CTL (Cytotoxic T-lymphoctyes)CTLs are the major immune defense

mechanism against tumors

CTLs recognize peptides derived from cytoplasmic proteins that are displayed bound to class I major histocompatibility complex (MHC) molecules

CTLs play a protective role against virus-associated neoplasms (e.g., EBV- and HPV-induced tumors)

Host Response to Tumors

NK cellsare capable of destroying tumor cells

without prior sensitization – 1st line defense against tumor cells

After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumors

recognize stress-induced antigens that are expressed on tumor cells and cells that have incurred DNA damage and are at risk for neoplastic transformation

Host Response to Tumors

MacrophagesActivated macrophages exhibit

cytotoxicity against tumor cells in vitro

Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes

(e.g., production of reactive oxygen metabolites or by secretion of TNF)

Host Response to Tumors

T cells, NK cells, and

macrophages may collaborate

in antitumor reactivity

interferon-γ, a cytokine

secreted by T cells and NK

cells, is a potent activator of

macrophages

Host immune response evasion by tumor cells

Selective outgrowth of antigen-negative

variants

loss or reduced expression of

histocompatibility antigensLack of costimulation ImmunosuppressionAntigen maskingApoptosis of cytotoxic T cells

Host immune response evasion by tumor cells

Selective outgrowth of antigen-negative

variants

- during tumor progression, strongly immunogenic

subclones may be eliminated loss or reduced expression of

histocompatibility antigens

- tumor cells may fail to express normal levels of HLA

class I molecules, thereby escaping attack by

cytotoxic T cells Such cells, however, may trigger NK

cells

Host immune response evasion by tumor cells

Lack of costimulation - sensitization of T cells requires two

signals, one by a foreign peptide

presented by MHC molecules and the

other by costimulatory molecules

- although tumor cells may express

peptide antigens with class I molecules,

they often do not express costimulatory

molecules

Host immune response evasion by tumor cells

Immunosuppression-Many oncogenic agents (e.g., chemicals

and ionizing radiation) suppress host

immune responses-Tumors or tumor products also may be

immunosuppressive. For example, TGF-β,

secreted in large quantities by many

tumors, is a potent immunosuppressant

Host immune response evasion by tumor cells

Antigen masking-The cell surface antigens of tumors may be

hidden, or masked, from the immune system by

glycocalyx molecules, such as sialic acid–containing

mucopolysaccharides

Apoptosis of cytotoxic T cellsSome melanomas and hepatocellular carcinomas

express FasL. It has been postulated that these

tumors kill Fas-expressing T lymphocytes that

come in contact with them, thus eliminating tumor-

specific T cells

Immunodiagnosis

Tumor antigens useful as tumor markers

released only from tumor tissue

Specific for a given tumor type

Has direct relationship to the tumor cell

Present in all patients with tumor

Tumors release antigen macromolecules that can be detected in vivo and in vitro

Immunodiagnosis

Examples of tumor antigens used for tumor markers

Alpha-Fetoprotein

Beta-subunit of human chorionic gonadotropin (B-HCG)

Prostate-specific antigen (PSA)

CA 125

Radio-labeled monoclonal antibody B72.3

Carcinoembryonic Antigen (CEA)

Immunodiagnosis

Immunohistochemistry Categorization of undifferentiated

malignant tumors

Determination of site of origin of

metastatic tumors

Detection of molecules that have

prognostic or therapeutic significance

Immunotherapy

Adoptive T cell therapy (AIT)

Passive immunotherapy using antibodies

Active-specific immunotherapy by using

vaccines

Passive immunotherapy: mAbs

Herceptin: anti-HER-2/neu in breast cancer patients

Rituximab: anti-CD20 in patients with non-Hodgkin’s lymphoma

Limitations: clearance by soluble Ags, antigenic variation of the tumor, inefficient killing or penetration into the tumor mass