Immunosurveillance

role of immunosurveillance in tumour immunity and tumour evasion mechanisms

1. IMMUNOSURVEILLANCE Presented by: Dr. Paripurna Baruah, 2 nd yr. PGT Microbiology Moderator: Dr. Dipa Barkataky, Prof. deptt . Of Microbiology

2. OVERVIEW Definition History Mechanisms of immune response Tumour antigens Mechanisms of immune evasion Summary References

3. DEFINITION IMMUNOSURVEILLANCE IS A CONCEPT THAT ENVISAGES PREVENTION OF THE DEVELOPMENT OF MOST TUMOURS THROUGH EARLY DETECTION OF ABNORMAL CELLS BY THE HOST’S IMMUNE SYSTEM.

4. HISTORY

5. The immune surveillance theory was first conceptualized in the early 1900s by Paul Ehrlich. He suggested that cancer cells frequently arise in the body but are recognized as foreign and eliminated by the immune system . He stated that: “in the enormously complicated course of foetal and post-foetal development, aberrant cells become unusually common. Fortunately, in the majority of people, they remain completely latent thanks to the organism’s positive mechanisms.” This hypothesis was not proven experimentally at the time due to the inadequacy of experimental tools and knowledge.

6. Some 50 years later, Lewis Thomas suggested that the cell-mediated branch of the immune system had evolved to patrol the body and eliminate cancer cells. According to these concepts, tumours arise only if cancer cells are able to escape immune surveillance, either by reducing their expression of tumour antigens or by an impairment in the immune response to these cells.

7. Sir Frank Mac Farlane Burnet hypothesized that tumour cell neo-antigens induce an immunological reaction against cancer and subsequently formulated the immune surveillance theory. He wrote that: “It is by no means inconceivable that small accumulation of tumour cells may develop and because of their possession of new antigenic potentialities provoke an effective immunological reaction with regression of the tumour and no clinical hint of its existence.”

8. However, the theory of immunosurveillance was imperfect, because, tumours do develop in the presence of a functioning immune system. Therefore, in 2002, the updated concept of CANCER IMMUNOEDITING was developed by Dr. Robert D. Schreiber.

9. HOW DOES IMMUNOSURVEILLANCE WORK?

10. The immune system is a remarkably versatile defense system that has evolved to protect animals from invading pathogenic microorganisms and cancer.

11. HUMORAL IMMUNE RESPONSE The effectors of the humoral branch are secreted antibodies, highly specific molecules that can bind and neutralize antigens on the surface of cells and in the extracellular spaces. The primary domain of antibody protection lies outside the cell. CELL MEDIATED IMMUNE RESPONSE The principal role of cell-mediated immunity is to detect and eliminate cells that harbour intracellular pathogens. Cell-mediated immunity also can recognize and eliminate cells, such as tumour cells, that have undergone genetic modifications so that they express antigens not typical of normal cells.

12. Cytotoxic T lymphocytes. Cytotoxic T lymphocytes, or CTLs, are generated by immune activation of T cytotoxic (T C ) cells. These effector cells have lytic capability and are critical in the recognition and elimination of altered self-cells (e.g., virus-infected cells and tumour cells) and in graft-rejection reactions. In general, CTLs are CD8+ and are therefore class I MHC restricted, although in rare instances CD4+ class II–restricted T cells have been shown to function as CTLs. Since virtually all nucleated cells in the body express class I MHC molecules, CTLs can recognize and eliminate almost any altered body cell.

13. Cytotoxic t lymphocytes KILL IN TWO WAYS

14. Directional delivery of cytotoxic proteins that are released from CTLs and enter target cells .

15. These granules contain: PERFORINS - 65kDa monomers of pore forming protein GRANZYMES/ FRAGMENTINS : serine proteases.

16. Interaction of the membrane-bound Fas ligand on CTLs with the Fas receptor on the surface of target cells

17. Natural Killer Cells Natural Killer Cells make up 5- 10% of the circulating lymphocyte population. These cells are involved in immune defences against viruses and tumours. Because NK cells produce a number of immunologically important cytokines, they play important roles in immune regulation and influence both innate and adaptive immunity. In particular, IFN-Y production by NK cells can affect the participation of macrophages in innate immunity by activation of the phagocytic and microbicidal activities. NK cells are the first line of defense against virus infection, controlling viral replication during the time required for activation, proliferation, and differentiation of CTL-P cells into functional CTLs at about day 7.

18. Natural killer cells appear to kill tumour cells and virus- infected cells by processes similar to those employed by CTLs. Despite these similarities, NK cells differ from CTLs in several significant ways. First, NK cells do not express antigen- specific T-cell receptors Recognition of target cells by NK cells is not MHC restricted. NK-cell response generates no immunologic memory.

19. how do natural killer cells recognize a target?

20. An activation receptor (AR) on NK cells interacts with its ligand on normal and altered self-cells. However, engagement of inhibitory NK cell receptors by class I MHC molecules delivers an inhibitory signal that counteracts the acti - vation signal. Expression of class I molecules on normal cells thus prevents their destruction by NK cells. Class I expression is often decreased on altered self-cells, the killing signal predominates, leading to their destruction.

21. ANTIBODY DEPENDANT CELL MEDIATED CYTOTOXICITY Antibodies are the antigen- binding proteins secreted by plasma cells and are present on the B- cell membrane. A number of cells that have cytotoxic potential express membrane receptors for the Fc region of the antibody molecule. When antibody is specifically bound to a target cell, these receptor-bearing cells can bind to the antibody Fc region, and thus to the target cells, and subsequently cause lysis of the target cell. Although these cytotoxic cells are nonspecific for antigen, the specificity of the antibody directs them to specific target cells. This type of cytotoxicity is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC).

22. Antibody-Dependent Cell-Mediated Cytotoxicity Lytic enzymes Perforin TNF Granzymes

23. TUMOUR ANTIGENS antigens on tumour cells and the immune response to these antigens.

24. Main classes of tumour antigens Products of mutated oncogenes and tumour suppressor genes. Products of other mutated genes. Over expressed or aberrantly expressed cellular proteins. Tumour antigens produced by oncogenic viruses. Oncofetal antigens. Altered cell surface glycolipids and glycoproteins. Cell type-specific differentiation antigens.

25. Products of mutated oncogenes and tumour suppressor genes Neoplastic transformation, results from genetic alterations in proto- oncogenes and tumour suppressor genes; these mutated genes encode variant proteins that have never been seen by the immune system and are thus recognized as non- self. They may enter the class I MHC antigen-processing 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 tumour cells, and thus be recognized by CD4+ T cells also.

26. Over expressed or aberrantly expressed cellular proteins Tumour antigens may also be normal cellular proteins that are abnormally expressed in tumour cells. It may be surprising that the immune system is able to respond to this normal self-antigen. The probable explanation is that these antigens are normally produced in such small amounts and in so few normal cells that it is not recognized by the immune system and fails to induce tolerance. One such antigen is tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas.

27. Tumour antigens produced by oncogenic viruses Several viruses are associated with cancers. Not surprisingly, these viruses produce proteins that are recognized as foreign by the immune system. The most potent of these antigens are proteins produced by latent DNA viruses; examples in humans include human papilloma virus (HPV) and Epstein-Barr virus (EBV). There is abundant evidence that CTLs recognize antigens of these viruses and that a competent immune system plays a role in surveillance against virus-induced tumours because of its ability to recognize and kill virus-infected cells. In fact, the concept of immune surveillance against tumours is best established for DNA virus- induced tumours.

28. How important are microorganisms in human cancer?

29. TUMOUR ORGANISM Adult T cell leukemia Human T Leukemia Virus I(HTLV I) Burkitt’s lymphoma & lymphoma in immunosuppression Nasopharyngeal cancer EBV Cervical cancer Human papilloma virus (HPV 16 & 18 and others) Liver cancer Hepatitis B and C Skin cancer Probably HPV Gastric carcinoma Helicobacter pylori

30. Oncofetal antigens Oncofoetal antigens are proteins that are expressed at high levels on cancer cells and in normal developing (foetal) tissues. Although originally believed to be completely specific for tumours and foetal tissues, as techniques for detecting these antigens have improved, it became clear that their expression in adults is not limited to tumours. Amounts of these proteins are increased in tissues and in the circulation in various inflammatory conditions, and they are even found in small quantities in normal tissues. There is no evidence that oncofoetal antigens are important inducers or targets of antitumor immunity.

31. Oncofetal antigens However, oncofoetal proteins are sufficiently specific that they can serve as markers that aid in tumour diagnosis and clinical management. The two most thoroughly characterized oncofoetal antigens are carcinoembryonic antigen (CEA) and ⍺-fetoprotein (AFP).

32. Altered cell surface glycolipids and glycoproteins. Most human and experimental tumours express higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids, which may be diagnostic markers and targets for therapy. Several mucins have been the focus of diagnostic and therapeutic studies, including CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on both ovarian and breast carcinomas.

33. Cell type-specific differentiation antigens. Tumours express molecules that are normally present on the cells of origin. These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types. Such differentiation antigens are typically normal self-antigens, and therefore they do not induce immune responses in tumour-bearing hosts. Their importance is as potential targets for immunotherapy and for identifying the tissue of origin of tumours.

34. Although the immune system clearly can respond to tumour cells, the fact that so many individuals die each year from cancer suggests that there are several mechanisms by which tumour cells appear to evade the immune system.

35. MECHANISMS DEVELOPED BY TUMOUR CELLS TO EVADE IMMUNOSURVEILLANCE .

36. SELECTION OF LESS IMMUNOGENIC/ ANTIGEN NEGATIVE VARIANTS

37. Down-regulation of class I MHC expression on tumour cells may allow a tumour to escape CTL-mediated recognition.

38. Antigen masking Presumably the antibody binds to tumour-specific antigens and masks the antigens from cytotoxic T cells. In many cases, the blocking factors are not antibodies alone but rather antibodies complexed with tumour antigens. The mechanism of this inhibition is not known. The complexes also may inhibit ADCC by binding to Fc receptors on NK cells or macrophages and blocking their activity.

39. Activation of immunoregulatory pathways T H -cell recognition of an antigenic peptide–MHC complex sometimes results in a state of non responsiveness called clonal anergy, marked by the inability of cells to proliferate in response to a peptide-MHC complex. This happens in the absence of a co-stimulatory signal , such as that produced by interaction of CD28 on T H cells with B7 on antigen-presenting cells. Through various mechanisms, tumour cells may downregulate the expression of co-stimulatory factors on APCs, making the tumour cell poorly immunogenic.

40. Immunosuppression Tumours may secrete several products that inhibit the host immune response. TGF-beta is secreted in large quantities by many tumours and is a potent immunosuppressant. Other such molecules secreted by tumour cells are : Galectins, Interleukin-10, Prostaglandin E2, certain metabolites derived from Tryptophan And VEGF.

41. s ome studies suggest that tumors produce factors that favor the development of immunosuppressive regulatory T cells, which could also contribute to "immune evasion."

42. TUMOUR CELL SECRETION OF CD95/ FASL ACTIVATION OF EFFECTOR T CELLS ACTIVATION OF EFFECTOR T REG CELLS DONOT EXPRESS C-FLIP EXPRESS C- FLIP CELL DEATH ESCAPE CELL DEATH SELECTIVE ACCUMULATION OF IMMUNOSUPRESSIVE T REGS

43. SUMMARY The immune system is a remarkably versatile defense system that has evolved to protect animals from invading pathogens and cancer. As conceptualized by Paul Ehrlich, as early as 1909, it is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminating not only a variety of foreign invaders, but also a number of aberrant cells arising from complex fetal and post- fetal development. These cells and molecules act together in a dynamic network whose complexity rivals that of the nervous system. However, cancer continues to be one of the major causes of death worldwide, meaning that the theory of immunosurveillance, albeit convincing, is not entirely perfect. Attempts on augmentation of the natural defense mechanisms of the body is one major approach to making cancer a curable disease.

44. Thank you

45. REFERENCES Delves PJ, Martin SJ, Burton DR, Roitt IM. Essential immunology . Sixth edition.John Wiley & Sons; 1988. Owen JA, Punt J, Stranford SA. Kuby immunology .sixth edition. New York: WH Freeman; 2006. Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran pathologic basis of disease. ninth edition. elsevier health sciences;2014. Swann JB, Smyth MJ. Immune surveillance of tumors. The Journal of clinical investigation. 2007 May 1;117(5):1137-46. Ribatti D. The concept of immune surveillance against tumors : The first theories. Oncotarget . 2017 Jan 24;8(4):7175- 7180.