Tumour Immunology: What happens when Good Cells go Bad.

1. Tumour Immunology:What happens when Good Cells go Bad. Dr Alasdair Fraser Sylvia Aitken Research Fellow Section of Experimental Haematology, Glasgow Royal Infirmary

2. Prevalence of cancer in UK

3. US Mortality, 2002 No. deaths % of all deaths Rank Cause of Death 1. Heart Diseases 696,947 28.5 2. Cancer 557,271 22.8 3. Cerebrovascular diseases 162,672 6.7 4. Chronic lower respiratory diseases 124,816 5.1 5. Accidents (Unintentional injuries) 106,742 4.4 6. Diabetes mellitus 73,249 3.0 7. Influenza and pneumonia 65,681 2.7 8. Alzheimer disease 58,866 2.4 9. Nephritis 40,974 1.7 10. Septicemia 33,865 1.4 Source: US Mortality Public Use Data Tape 2002, National Center for Health Statistics, CDCP, 2004.

4. Men710,040 Women662,870 2005 Estimated US Cancer Cases 32% Breast 12% Lung / bronchus 11% Colon / rectum 6% Uterine corpus 4% Non-Hodgkin’s 4% Melanoma of skin 3% Ovary 3% Thyroid 2% Urinary bladder 2% Pancreas 21% All Other Sites Prostate 33% Lung / bronchus 13% Colon / rectum 10% Urinary / bladder 7% Melanoma of skin 5% Non-Hodgkin’s 4% Kidney 3% Leukemia 3% Oral Cavity 3% Pancreas 2% All Other Sites 17% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2005.

5. Men295,280 Women275,000 2005 Estimated US Cancer Deaths 27% Lung and bronchus 15% Breast 10% Colon and rectum 6% Ovary 6% Pancreas 4% Leukemia 3% Non-Hodgkin’s 3% Uterine corpus 2% Multiple myeloma 2% Brain / ONS 22% All other sites Lung / bronchus 31% Prostate 10% Colon / rectum 10% Pancreas 5% Leukemias 4% Esophagus 4% Liver / bile duct 3% Non-Hodgkin’s 3% Urinary / bladder 3% Kidney 3% All other sites 24% ONS=Other nervous system. Source: American Cancer Society, 2005.

6. Site 1974-1976 1983-1985 1995-2000 Relative Survival (%) during Three Time Periods All sites 50 53 64 Breast (female) 75 78 88 Colon 50 58 63 Leukemia 34 41 46 Lung and bronchus 13 14 15 Melanoma of the skin 80 85 91 Non-Hodgkin lymphoma 47 54 59 Ovary 37 41 44 Pancreas 3 3 4 Prostate 67 75 99 Rectum 49 55 64 Urinary bladder 73 78 82 *5-year relative survival rates based on follow up of patients through 2001. Source: SEER Program (1975-2001), NCI 2004.

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

8. 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

9. Evidence for IR to tumours Animal models showed that pre-treatment of mice with killed tumour material could protect against a subsequent challenge. T cell ablation or T-cell deficient mice removed this protection. Transfer of T cells from an immunized mouse could protect a naïve mouse from tumour challenge.

10. 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)

11. ...................................................... IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity Vijay Shankaran*, Hiroaki Ikeda*, Allen T. Bruce*, J. Michael White*, Paul E. Swanson*, Lloyd J. Old² & Robert D. Schreiber* ............................................................................................................................................. 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

12. 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.

13. Innate control of cancer

14. 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.

15. 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)

16. 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

17. 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

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

19. 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

20. 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

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

22. Evasion Mechanisms

23. 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?

24. Anti-cancer Therapies and the IR

25. 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.