Tumour Immunology: What happens when Good Cells go Bad.

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

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

Host Defense Against Tumor Tumor 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.

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

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

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

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

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

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

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)

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

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.

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.

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

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

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

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

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

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

Three Es of Immunoediting CTL NKT NK CD4 NKCTL CD4 NK CTL EliminationEquilibriumEscape Genetic instability / tumour heterogeneity

Evasion Mechanisms

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

Anti-cancer Therapies and the IR CategoryExampleEffectIR Radiation γ / αBM ablation/ localised X Alkylating Cyclo- phosphamide DNA X-linking X Anti-metabolites 5-FU Ara-C/Ara-A Inhibit DNA synthesis X Natural products Taxanes Vinca alkaloids Mycins DNA damage or microtubule inhibitors X Metals Cisplatin arsenicals DNA X-linking and cytotoxicity X New drugs Imatinib Thalidomide Signalling inhibitor +/-

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.