Tumour Immunology: What happens when Good Cells go Bad.

1. Tumour Immunology:What happens when Good Cells go Bad.

2. Host Defense Against TumorTumor Immunity Definition coordinated biologic process designed to recognize tumor cells and their products and to kill or damage the offending cells.

3. Spontaneous UV and ionizing radiation Chemical carcinogens Tumour induction Genetic abnormalities (XP) Virus-induced (HepC, EBV, HPV) Immunosuppression Causative agents

4. Host Defense Against TumorTumor Immunity Tumor Specific Antigens (TSA) Present only on tumor cells and not on any normal cells and can be recognized by cytotoxic T-lymphocytes. Tumor Associated Antigens (TAA) Not unique to tumors and are also see on normal cells.

5. Tumor Antigens Tumor Specific Antigens (TSA) Cancer testis antigen Viral antigen Mucin Oncofetal antigens Antigens resulting from mutational in protein B catenin, RAS, P53,CDK4

6. Tumor Antigens Tissue Associated Antigen=TAA Present in normal cells & tumor cells e.g. MART-1, gp100, tyrosinase expressed in melanomas & normal melanocytes T-cells directed against melanomas will also destroy normal melanin containing cells

7. Tumor Antigens Tumor Associated Antigens(TAA) MART-1, gp100, tyrosinase Over expressed antigens Differentiation- specific antigens

8. Tumor Associated Antigens(TAA) Over expressed Antigens e.g HER-2 (neu) in 30 % Breast cancer ( present in normal breast & ovary)

11. Tumor Associated Antigens(TAA) Differentiation- Specific Antigens e.g CD10& PSA Expressed in normal B cells & Prostate Used as a marker for tumors arise from these cells

12. How do cancer cells differ from normal? • Clonal in origin • Deregulated growth and lifespan • Altered tissue affinity • Resistance to control via apoptotic signals • Change in surface phenotype and markers • Structural and biochemical changes • Presence of tumour-specific antigens

13. Immune Surveillance of Cancer • Proposed originally in 1909 by Paul Ehrlich • Refined in late 1950s by Burnet and Thomas “In animals…genetic changes must be common and a proportion…will represent a step towards malignancy. …there should be some mechanism for eliminating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character.” FM Burnet “The concept of immunological surveillance” (1970)

14. Immune Surveillance of Cancer • Subsequent evidence against immune surveillance, particularly from nude mice studies. • More recent studies identify effector populations and KO models utilised. • Definitive evidence of immune surveillance published by Schreiber et al in 2001

15. Evidence of Immune Surveillance in Humans • Immunosuppression leads to increased development of viral-derived tumours (Kaposi / NHL / HPV). • Organ transplant increases malignant melanoma risk. (0.3% general paediatric popn., 4% paediatric transplants) • 3-fold higher risk of sarcoma. • High TIL presence correlates with improved survival. • NK or γ/δ T cell loss correlates with increased tumour pathogenicity.

16. NK cell control of cancer in humans • NK / NKT cells in animal models destroy tumours with down-regulated Class I expression. • Control of haematological malignancy after haplotype-mismatched BM/SC transplant Costello et al (2004) Trends Immunol. • Maintenance of remission in acute leukaemias dependent upon CD56+/CD8α+ NK cells Lowdell et al (2002) Br.J.Haematol.

17. Antigens involved in tumour recognition Tumour-specific antigens • Bcr-abl (CML) • CDK-4 / β-catenin (melanoma) Testes-specific antigens • MAGE 1-3 (melanoma) • NY-ESO-1 (melanoma) Differentiation antigens • Tyrosinase (TRP-1/2) • Melan-A (melanoma) • Monoclonal Ab (myeloma) Tumour associated antigens • MUC-1 (myeloma etc) • α-fetoprotein (many) • Her-2/neu (breast) • WT-1 (many) • myeloblastin (leukaemias) • Survivin (many)

18. Tumour cell present CTL CTL APC Broken up to release antigens How does the adaptive IR target tumours? Ab / ADCC / cytokine attack Th B Th cells educate other T/B cells APC recruits T cells able to recognise tumour antigens CTL recognise and destroy other tumour cells T T

19. Effector mechanisms against cancer • Monocyte / macrophage release lytic enzymes and phagocytose necrotic material • Antibody against tumour antigens • Induction of tumour-specific CTL and TIL • Initiation of NK / CTL cytotoxic responses • Release of cytokines / chemokines (TNFα, IFNs etc) and antiangiogenic factors

20. CTL Direct CTL / NK attack FasL Perforin Granzyme B TCR Fas (CD95) Class I + Ag TUMOUR CELL

21. NKT NKT NKT NK CTL γδ T γδ T NK NK NK CD4 CTL NK CTL CD4 CTL CXC10-12 IFNγ IFNγ LN CXC10-12 IFNγ NK cells and other effectors recruited to site by chemokines, which also target tumour growth directly. Tumour-specific T cells home to tumour site, along with macrophages and other effectors to eliminate tumour cells. DC DC Innate IR recognises tumour cell establishment MΦ MΦ MΦ IR-Mediated Tumour Elimination

22. Immunoediting- The Great Escape! • Strong evidence that IR controls and eradicates nascent cancer cells • “Immunoediting” eventually produces low antigenicity tumour cells • Pressure from immune system coupled with genomic instability selects for escape

23. Three Es of Immunoediting Elimination Equilibrium Escape NKT CD4 CTL NK NK NK CTL CTL CTL CD4 Genetic instability / tumour heterogeneity

24. Evasion Mechanisms

25. myeloma cancer cell MM cell release factors which ‘turn off’ T cells T APC recruits CTL specific for myeloma Ag APC T cells recognise and destroy other cancer cells Broken up to release antigens T T T T How does MM evade the immune response?

26. Anti-cancer Therapies and the IR

27. Summary • Cancers are one of the leading causes of death throughout the world. • Tumours arise from single events (spontaneous / viral / induced) and altered characteristics produce unregulated growth. • Majority of tumours dealt with by IR before development progresses to clinical stage. • Immunoediting leads to development of escape clones. • Established tumours can prevent immune attack in the absence of further triggers.