Cancer Immunoediting Integrating Immunity ’ s Roles in Cancer Suppression and Promotion

1. CancerImmunoeditingIntegratingImmunity’sRoles in CancerSuppressionandPromotion Omer GULLULU

2. The immune systemplays a dual role in cancer: • Destruction • Provide a hostregion

3. BurnetandThomas built their cancerimmunosurveillance hypothesis,a concept that formally envisaged thatadaptiveimmunity was responsible for preventingcancer development in immunocompetenthosts.

4. Stutmanprovided little support for thishypothesis. Ofparticular note were experimentsshowing thatthe cancersusceptibility of immunocompetentmice(toboth spontaneous and carcinogen-inducedtumors)was similar to that of nude mice thathadmajor but not total immunodeficiency

5. Three views; • Tumor cells did not possess the appropriate “danger signals” needed to alert the immune system to the presence of a foreign cell. • The immune system would ignore or be tolerant to a developing tumor because tumor cells were too similar to the normal cells from which they were derived. • Pro-inflammatory arm of immunity could facilitate cellular transformation and promote cancer outgrowth and argued that this effect of immunity precluded its capacity to fulfill a protective function.

6. Effects of INF-γand STAT1 The discovery of the importance ofinterferon-gamma(IFN-γ) in promoting immunologicallyinduced rejection of transplanted tumorcells and by the demonstration that mice lackingeither IFN-γresponsiveness (gene-targetedmice lacking either the IFN-γreceptor or theSTAT1 transcription factor required for IFN receptorsignaling) or adaptive immunity [RAG2−/−mice lackingT cells, B cells, and natural killerT (NKT)cells]weremore susceptible tocarcinogeninducedand spontaneous primary tumor formation.

8. DistinctRoles of ImmuneSystem • It protects the host against viral infection • It prevents thetumorigenesis • It eliminatestumor cells in certain tissues

9. Tumor Antigens and Cancer Immunosurveillance Cancercellsexpressantigens ?

10. In the case of human cancer, identification oftumor antigens required the development ofnovel in vitro detection and cloning methodsthat used as probes antibodies and cytolyticTlymphocytes (CD8 T cells) derived fromcancer patients that were specific for theautologous tumor.

11. Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.

12. Thehumantumorantigens; • Differentiationantigens (such as melanocytedifferentiationantigens) • Mutationalantigens (such as p53) • Overexpressedcellularantigens (such as HER-2 (Human Epidermal Growth Factor Receptor 2)) • Viralantigens (such as humanpapillomavirusproteins) • Cancer/testis (CT) antigens

13. TheCancerImmunoeditingHypothesis Notonly tumor quantity but also tumor quality

14. The notion that the immune system not only protects the host against tumor formation but also shapes tumor immunogenicity is the basis of the cancer immunoediting hypothesis, which stresses the dual host-protective and tumor-promoting actions of immunity on developing tumors.

16. Thecancerimmunoeditingprocessproceedsthroughthreedistinctphases:Thecancerimmunoeditingprocessproceedsthroughthreedistinctphases: • Elimination • Equilibrium • Escape

18. Immunosuppressivecytokines; • Vascularendothelialgrowthfactor (VEGF) • Transforminggrowthfactor–β (TGF-β) • Galectin • Indoleamine2,3-dioxygenase (IDO)

19. Regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSCs) are two major types of immunosuppressive leukocyte populations that play key roles in inhibiting host-protective antitumor responses.

20. Thenegativeco-stimulatorycytokines; • CTLA-4 (Cytotoxic T-LymphocyteAntigen4) • Programmed cell death protein 1 (PD-1) • PD-L1 • PD-L2 • Interleukin 2 (IL-2)

23. CancerImmunoeditingVersusInflammation Inducingcellularproliferation Genotoxicstress – (Cancerpromotion) EnhancingangiogenesisTissueinvasion Cancerprogression ChronicinflammationTumorigenesis

24. Pro-inflammatorycytokines/signaling Control components of immunity • IL-1β • IL-23 • MyD88 • IFN-γ • IFN-α/β • IL-12 • T cells Interaction

25. MyD88 and IL-1β • Promotecarcinogen-induced tumorigenesis ? • Promotedevelopment of protective immune responses against established tumors by facilitating recognition of tumor cells undergoing “immunogenic death” ?

26. TumorNecrosisFactor-Alpha ( TNF-α) Regulators of G-Protein Signaling (RGS) IntraOcularPressure-InducedIschemia (IOP Ischemia)

27. CancerImmunoediting in Humans • Intratumoral immune responsespredictpatientprognosis CD4+ T cells PromoteTumor Control IFN-γ CD8+ T cells TNF-α

28. Spontaneousimmuneresponses in cancerpatients • Paraneoplasticneurologicdisorders (PNDs). PNDsarise as a consequence of antibody and T cellresponsesagainstcertainautologoustumorsthatectopically express proteins normally expressedonly in cells of the nervous system.

29. Immunodeficiency is associated with a higher risk of cancer • Immunodeficiency has beenlinkedto increased cancer risk in patients with AIDSandin transplant recipients maintained onimmunosuppressants. • Insights into the role of the immune system inhumancancer have also come from anecdotalreports ofcancer being transferred from an organdonor to the immunosuppressed recipient.

30. Thanks