Tumor antigens & cancer immunotherapy.pptx

Tumor antigens and cancer immunotherapy

1. Present by, D.Ragavi M .Sc.Biochemistry

2. Tumor antigen and cancer immunotherapy

3. What is tumor ? How does it occur?

4. TUMOR ANTIGEN

5. What are tumor antigens? Tumor antigens are proteins, glycoproteins, glycolipids, or carbohydrates expressed on the surface of tumor cells. Tumor antigens are unique substance present on tumor cell. Tumor antigens are useful markers in cancer diagnosis. It can be a potential target for use in cancer therapy. Tumor antigens are produced from mutation, over expression of normal proteins and some oncogenic viruses.

6. TYPES OF TUMOR ANTIGEN Two types of tumor antigens are identified. (i) Tumor specific transplantation antigens ( TSTAs ) (ii) Tumor associated transplantation antigens ( TATAs )

7. TUMOR SPECIFIC TRANSPLANTATION ANTIGENS ( TSTAs ) 1. Unique to tumor cells 2. Do not occur on normal cells in the body. 3. TSTA produced due to physical, chemical or viral mutagens 4. Mutation results in altered cellular proteins. This cellular proteins on cytosolic processing results in novel peptides i.e. tumor antigen 5 . This tumor antigen induces cell-mediated immune response by tumor-specific cytosolic T-cell (CTLS) . 6 . The immune system detects and eliminates these tumor cells by the antigens on the cell surface.

8. TUMOR ASSOCIATED TRANSPLANTATION ANTIGENS (TATAs ) 1.Tumor-associated antigens are not unique to tumor cells. 2.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. Reactivation of the embryonic genes that encode oncofetal proteins in tumor cells results in their expression on the fully differentiated tumor cells. 4.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.

9. CLASSIFICATION BASED ON T CELL RECOGNIZATION Antigens encoded by genes exclusively expressed by tumors Antigens encoded by variant forms of normal genes that have been altered by mutation Antigens normally expressed only at certain stages of differentiation or only by certain differentiation lineages Antigens that are overexpressed in particular tumors

10. IMMUME RESPONSE AGAINST TUMOR Tumor antigens can induce both humoral and cell – mediated immune response resulting in the destruction of tumor cells. Among these the cell mediated immune response plays a major role. Many tumors have been shown to induce tumor specific CTLs that recognize tumor antigens presented by class – I MHC on the tumor cells.

11. IMMUNE RESPONSE AGAINST TUMOR

12. ELIMINATION OF TUMOR CELLS Over the past decade there has been notable progress in the concept of cancer immunosurveillance and immunoediting. CANCER IMMUNOSURVEILLANCE It is an important host protection process that inhibits carcinogenesis and maintain regular cellular homeostasis. CANCER IMMUNOEDITING It is a process by which a person is protected from cancer growth and the development of tumor immunogenicity by their immune system.

13. It has three main phase: (i) Elimination phase (ii) Equilibrium phase (iii) Escape (i). Elimination phase Phase -I: The first phase of elimination Involves the initiation of antitumor immune response.During this phase, the intilitating lymphocytes such as the natural killer cells and natural Killer T cells Stimulated to produce IEN - gamma . phase - II : Newly Synthesisod IFN - gamma induce tumor death (to a limited amount)as well as Promotion of chemokines. These chemokines play an important role in promoting tumor death by blocking the Formation of new blood vessels. Tumor cell debrets produced as a result of tumor death is then ingested by dentrcetic cells, Followed by the migration of these dendritic cells to the draining lymph nodes.

14. The recruitment of more Immune cells also ouccurs and is mediated by the chemokines produced during the Inflammatory process. Phase – III : Natural killer cells and macrophage transactive one another via the reciprocal production of IFN- gamma and IL -12.In the draining lymph nodes, tumor – specific dendritic cells trigger the diffrentiation of TH cells which in turn facilitates the development of CD8+ Tcall phase - IV : tumor - Specific CD4+ land CD8 +T cells home to the tumor site and the cytotoxic T lymphocytes then destroy the antigen - bearing tunon cells which remain at the site.Equlibrium and Escape Tumor cell varients witch have survived the elimination phase enter the equilibrium phase.

15. Equilibrium and Escape phase : In this phase, lymphocytes land IFN - gamma exert a selection pressure on tumour cells which are genetically unstable and rapidly mutating. Tumor cell variants which have acquired resistances to equilibrium than enter the escape phase. In this phase , turmor cells continue to grow and expand in an uncontrolled mannel and may eventually lead to malignances.

16. ROLE OF NK CELLS The recognition of tumor cells by NK cells is not MHC restricted. Thus, the activity of these cells is not compromised by the decreased MHC expression exhibited by some tumor cells. In some cases, Fc receptor on NK cells can bind to antibody – coated tumor cells, leading to ADCC.

17. ROLE OF MACROPHAGES Macrophages are observed to cluster around tumors and their presence is often cause tumor regression. They carry out the same function as NK cells with the help of Fc receptor. These cells carry out their antitumour activity by secreting lytic enzyme, reactive nitrogen and intermediates, cytokine called Tumor Necrosis Factor ( TNF – α ) that have potent antitumor activity.

18. Manipulation of co-stimulatory signals can enhance immunity Several research group have demonstrated that tumor immunity can be enhanced by providing the co – stimulatory signal necessary for activation of CTL precursor ( CTL – Ps ) As human melanoma antigens are shared by a number of different human tumors, it might be possible to generate a panel of B7 – transfected melanoma cell lines that are typed for tumor – antigen Expression an for HLA expression. In this approach, the tumor antigens expressed by a patient’s tumor would be determined, and then the patient would be vaccinated with an irradiated B7 – transfected cell line that expresses similar tumor – antigen.

19. Enhancement of APC activity can modulate Tumor Immunity One approach that has been tried is to transfer tumor cells with the gene encoding GM-CSF. These engineered tumor cells, when reinforced into the patient will secrete GM – CSF, enhancing the differentiated and activation of host antigen-presenting cells, especially dendritic cells. Another way to expand the dentritric-cells population is to culture dentritic cells from peripheral- blood progenitor cells in the presence of GM – CSF, TNF – α and IL – 4. These three cytokine induce the generation of large numbers of dentritic cells.

20. C ytokine therapy can Augment Immune Responses to tumours 1. Cytocines that have been evaluated in cances immunotharapy are IFN- α, β and gamma ; IL- 1 ,IL - 2 ,IL - 4 , IL - 5 and IL -12 ; GM-CSF; and TNF. 2. Although these trails have produced occasional encouraging results, many obstacles remain to the Successful case of this type of cancer immunotherapy.

21. Interferons 1. Large auantitios of purified recombinant preparations of the interferon, IFN - α, IFN- β and IFN- Y are now available, each of which has shown some promise in the treatment of human cancer. 2. All three types of interte fe ron have been shown to increase class I MHC expression on tumor cells ; IFN -y has also been shown to increase class II MHC expression on macrophages.

22. Tu mor Necrosis Factors 1. In some instances, the tumor necrosis factors TNF - α vand TNF- β have been shown to exhibit direct anti tumor activity, killing some tumor cells and reducing the rate of proliferation of others while spacing normal cells. 2 . In the presence of TNF - α or TNF - β , a tumors undergoes visible hemorrhagic necrosis and regression. 3. TNF – α has also been shown to inhibit tumor – induced vascularisation ( angiogenesis ) by damaging the vascular endothelial cells in the vicinity of a tumor, thereby decreasing the flow of blood and oxygen that is necessary for progressive tumor grow.

23. Monoclonal antibodies are effective in treating some tumors