tumor antigen

TUMOR CELL

TUMOR ANTIGENS

TUMOR ANTIGE

NSWATHI PRABHAKAR[810014214042]III Year, B.Tech BiotechAnna university [BIT Campus]Trichy 620 [email protected]

OVERVIEW1.TUMOUR ANTIGEN2.CLASSIFICATION3.PROPERTIES3.1.Tumor-specific transplantation antigens (TSTAs)3.2. Tumor-associated transplantation antigens (TATAs)4.CLASSIFICATION BASED ON T -CELL RECOGNITION

5.TSTA PRODUCING AGENTS6.SPECIFICITY OF AGENTS IN TSTA 7.IDENTIFICATION OF TSTA INDUCING GENE8.CHARACTERIZATION OF TSTA

9.TUMOR-ASSOCIATED TRANSPLANTATION ANTIGENS (TATAS)-TYPES

10.IMMUNE RESPONSE AGAINST TUMOR11.NK CELLS IN TUMOR RECOGNITION12.MACROPHAGES IN TUMOR RECOGNITION14.IMMUNE SURVEILLANCE THEORY OBSERVATIONS

Tumor antigen is an antigenic substance produced in tumor cells. i.e., it triggers an immune response in the host. These antigens are not membrane proteins but are derivatives of cytosolic proteins.

i.e.,peptides of cytosolic proteins

1.TUMOUR ANTIGEN

2.CLASSIFICATION Two types of tumor antigens have been

identified on tumor cells:

1. Tumor-Specific Transplantation Antigens (TSTAs)

E.g. : Abnormal products of ras and p53 genes2. Tumor-Associated Transplantation Antigens

(TATAs) E.g. : Epidermal growth factor (EGF) like p97

2.CLASSIFICATIONTwo genes- red and blueTwo

proteins- red and blue

2.CLASSIFICATION

Mutated Pink gene

New altered protein

2.CLASSIFICATIONIrregular gene expression- Black colour

Unwanted protein production

2.CLASSIFICATIONOver expressed Normal gene

Abnormal protein concentration

3.PROPERTIES

1. Unique to tumor cells 2. Do not occur on normal cells in the body.3. TSTA produced due to physical, chemical or viral

mutagens4. Mutation results in altered cellular proteins. This

cellular proteins on cytosolic processing results in novel peptides i.e. tumor antigen

3.1.Tumor-specific transplantation antigens (TSTAs)

3.PROPERTIES

4. This tumor antigen induces cell-mediated immune response by tumor-specific cytosolic T-cell (CTLs)

5. The immune system detects and eliminates these tumor cells by the antigens on the cell surface.

3.1.Tumor-specific transplantation antigens (TSTAs)

3.PROPERTIES

• Tumor-associated antigens are not unique to tumor cells.

• These are proteins that are expressed on normal cells during fetal development when the immune system is immature and unable to respond but that normally are not expressed in the adult.

3.2. Tumor-associated transplantation antigens (TATAs)

3.PROPERTIES

• Reactivation of the embryonic genes that encode oncofetal proteins in tumor cells results in their expression on the fully differentiated tumor cells.

• Tumor-associated antigens may also be proteins that are normally expressed at extremely low levels on normal cells but are expressed at much higher levels on tumor cells.


3.PROPERTIES3.2. Tumor-associated transplantation

antigens (TATAs)

• For example, Transferrin growth factor, designated p97, which aids in the transport of iron into cells. Whereas normal cells express less than 8,000 molecules of p97 per cell, melanoma cells express 50,000–500,000 molecules of p97 per cell

3.PROPERTIES3.2. Tumor-associated transplantation

antigens (TATAs)

4.CLASSIFICATION BASED ON T -CELL RECOGNITION

1. Antigens encoded by genes exclusively expressed by tumors.

2. Antigens encoded by variant forms of normal genes that have been altered by mutation.

3. Antigens normally expressed only at certain stages of differentiation or only by certain differentiation lineages.

4. Antigens that are over expressed in particular tumors

4.CLASSIFICATION BASED ON T -CELL RECOGNITION


5.TSTA PRODUCING AGENTS

Following are causes of TSTA Production:

1. Chemical agents E.g. : Methylcholanthrene2. Physical agents E.g. : Ultraviolet light3. VIRUS E.g. : Polyoma virus (PV)

6.SPECIFICITY OF AGENTS IN TSTA

1. Chemical agents/ Physical agents -Antigens’ nature varies with respect to 1.1. The type of tissue administered 1.2. The dosage

2. VIRUS

- Antigens are specific only to strain irrespective of tissue and concentration.

6.SPECIFICITY OF AGENTS IN TSTA

7.IDENTIFICATION OF TSTA INDUCING GENE

8.CHARACTERIZATIONOF TSTA

• In one method, peptides bound to class I MHC molecules on the membranes of the tumor cells are eluted with acid and purified by high-pressure liquid chromatography (HPLC). In some cases, sufficient peptide is eluted to allow its sequence to be deduced by Edman degradation.

8.CHARACTERIZATION OF TSTA

In a second approach, cDNA libraries are prepared from tumor cells. These cDNA libraries are transfected transiently into COS cells, which are monkey kidney cells transfected with the gene that codes for the SV40 large-T antigen. When these cells are later transfected with plasmids containing both the tumor-cell cDNA and an SV40 origin of replication, the large-T antigen stimulates plasmid replication, so that up to 104–105 plasmid copies are produced per cell. This results in high-level expression of the tumor-cell DNA.

9.TUMOR-ASSOCIATED TRANSPLANTATION ANTIGENS (TATAS)-TYPES

1. ONCOFETAL TUMOR ANTIGENS E.g. :1. Alpha-fetoprotein (AFP) -Liver cancer 2.Carcinoembryonic antigen (CEA)- advanced

Colorectal cancer

2. ONCOGENE PROTEINS AS TUMOR ANTIGENS E.g. : Human breast-cancer cells -Neu protein

10.IMMUNE RESPONSE AGAINST TUMOR

Tumor antigens Cell-mediated immune responses

Humoral immune responses

IMMUNE SYSTEM

IMMUNE SYSTEM

(Major)

(Minor)

TSTAs CTLs produced against tumor antigens

But MHC count on tumor cells reduces thus limiting CTLs

Tumor antigens are displayed by class I MHC

10.IMMUNE RESPONSE AGAINST TUMOR

11.NK CELLS IN TUMOR RECOGNITION

The recognition of tumor cells by NK cells is MHCrestricted

Fc receptors on NK cells can bindto antibody-coated tumor cells, leading

to ADCC.

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11.NK CELLS IN TUMOR RECOGNITION

12.MACROPHAGES IN TUMOR RECOGNITION

The recognition of tumor cells by macrophages are not MHC restricted

Macrophages cluster around

Tumor cells

Mediates ADCC utilising lytic

enzymes, ROS,RNS.

Macrophages produces cytokine –“TNF alpha” induceing hemorrhage

and necrosis of the tumor.

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13.IMMUNE SURVEILLANCE THEORY

Immune surveillance theory conceptualized by Paul Ehrlich-states “cancer cells frequently arise in the body but are recognized as foreign and eliminated by the immune system”

Later Lewis Thomas suggested that the cell-mediated branch of the immune system had evolved to patrol the body and eliminate cancer cells.

Impairment in the immune response results in cancer.

13. IMMUNE SURVEILLANCE THEORY-CONTRARY STATEMENTS

1.Nude mice (Lacking thymus and functional T cells) shows no susceptible to cancer.

2. Individuals on immunosuppressive drugs do show an increased incidence of cancers of the immune system, other common cancers (e.g., lung, breast, and colon cancer) are not increased in these individuals, contrary to what the theory predicts

13. IMMUNE SURVEILLANCE THEORY-CONTRARY STATEMENTS

3. Effect of tumor-cell dosage on the ability of the immune system to respond also are incompatible with the immune surveillance theory. For example, animals injected with very low or very high doses of tumor cells develop tumors, whereas those injected with intermediate doses do not. The mechanism by which a low dose of tumor cells “sneaks through” is difficult to reconcile with the immune surveillance theory

13.IMMUNE SURVEILLANCE THEORY-OBSERVATIONS

1.Finally, this theory assumes malignant tumors arise only if the immune system is somehow impaired or if the tumor cells lose their immunogenicity, enabling them to escape immune surveillance

2. Cancer cells and normal cells exhibit qualitative antigen differences

3. An immune response can be generated to tumor cells, and therapeutic approaches aimed at increasing that response may serve as a defense against malignant cells tumor evasion of the Immune

ReasonObservation

AndExperience-the holy trinity of science

Lovingly SWATHI PRABHAKAR

-ROBERT GREEN INGERSOLL

tumor antigen

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