Tumour immunology & immunotherapy

1. Tumourimmunology & immunotherapy Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity.

2. The Immune System and Cancer • Cancercellshaveundergonetransformation, divide uncontrollably, and possestumor-associated antigens. • Immunologicalsurveillance – responseof immune system tocancercells • Cytotoxic T cells and NK cellsrecognize and lysecancerouscells. • Cancercellsmayescapeimmunosurveillance, maysuppress T cells, or maygrowfasterthan the immune system can respond.

3. Immunosurveillance • The spontaneous recognition and elimination of tumours by T cells • Cancer immunosurveillance appears to be an important host protection process that decreases cancer rates through:- inhibition of carcinogenesis;- maintaining of regular cellular homeostasis.

4. Immunoediting • Immunoediting is a process by which a person is protected from cancer growth and the development of tumour immunogenicity by their immune system. • It has three main phases: - Elimination- Equilibrium- Escape

5. Phase 1 • Initiationof an antitumor immune response. Cells of the innate immune system recognize the presence of a growing tumor which has undergone stromal remodeling, causing local tissue damage. This is followed by the induction of inflammatory signals which is essential for recruiting cells of the innate immune system to the tumor site. natural killer cells and natural killer T cells are stimulated to produce IFN-gamma.

6. Phase 2 • In the second phase of elimination, newly synthesized IFN-gamma induces tumor death (to a limited amount) as well as promoting the production of chemokines CXCL10, CXCL9 AND CXCL11. These chemokines play an important role in promoting tumor death by blocking the formation of new blood vessels.

7. Phase 3 • In the third phase, natural killer cells and macrophages transactivate one another via the reciprocal production of IFN-gamma and IL-12. This again promotes more tumor killing by these cells via apoptosis and the production of reactive oxygen and nitrogen intermediates. In the draining lymph nodes, tumor-specific dendritic cells trigger the differentiation of Th1 cells which in turn facilitates the development of CD8+ T cells also known as killer T-cells.

8. Phase 4 • In the final phase of elimination, tumor-specific CD4+ and CD8+ T cells home to the tumor site and the cytolytic T lymphocytes then destroy the antigen-bearing tumor cells which remain at the site.

9. Elimination

10. Equilibrium and Escape • Tumor cell variants which have survived the elimination phase enter the equilibrium phase. In this phase, lymphocytes and IFN-gamma exert a selection pressure on tumor cells which are genetically unstable and rapidly mutating. Tumor cell variants which have acquired resistance to elimination then enter the escape phase. In this phase, tumor cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies. In the study of cancer immunoediting, knockout mice have been used for experimentation since human testing is not possible. Tumor infiltration by lymphocytes is seen as a reflection of a tumor-related immune response

12. Elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer.

13. Cancer immunotherapy • a major goal of cancer immunotherapy has been to generate a large number of highly avid, tumor-specific T cells that can last in vivo for a long time and resist tolerization. Existing methods focus on reshaping the normal T cell repertoire and fall into 2 categories:

14. 1) Methods relying on massive expansion of the few antigen-specific T cells • Active immunotherapy, which involves activating the effectors in the host immune system to inhibit cancer cell growth and reject tumor (e.g., cancer vaccination) • Passive immunotherapy, which directly provides the host with effectors to react against cancer (e.g., adoptive transfer of in vitro expanded or modified anti-tumor T cells)

15. 2) Creating autologous T cells of a desired specificity with TCR gene transfer (instructive immunotherapy) • conventional TCR transgenicanimals • retrovirus-mediated expression of TCR genes in peripheral T cells • retrovirus-mediated expression of TCR genes in hematopoietic stem cells (HSCs)

16. 1)Zitvogel, L.; Tesniere, A.; Kroemer, G. (2006). "Cancer in spiteofimmunosurveillance: immunoselection and immunosubversion". Nat. Rev. Immunol 2)Dunn, G.P.; Bruce, A.T.; Ikeda, H.; Old, L.J.; Schreiber, R.D. (2002). "Cancerimmunoediting: fromimmunosurveillancetotumorescape". Nature Immunology 3) Kim, R.; Emi, M.; Tanabe, K. (2007). "Cancer immunoediting from immune surveillance to immune escape". Journal of Immunology 4) Dunn, G.P.; Old, L.J.; Schreiber, R.D. (2004). "The Three Es of Cancer Immunoediting". Annual Review of Immunology 5)Zitvogel, L.; Casares, N.; Péquignot, M.; Chaput, N; Albert, M.L.; Kroemer, G (2004). "The immune responseagainstdyingtumorcells".Adv. Immunol. Advances in Immunology