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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
Th
CTL
CTL recognise and destroy other
tumour cells
CTL
Th 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
IR-Mediated Tumour Elimination
γδ TNKT
NK
IFNγ
NK
NK
DCLN
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
MΦIFNγ
CTLCD4
CXC10-12
CTL
CTLCD4
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
CTL
NKT
NK
CD4
NK CTLCD4
NKCTL
Elimination Equilibrium Escape
Genetic instability / tumour heterogeneity
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
TT
T cells recognise and destroy other
cancer cells
MM cell release factors which
‘turn off’ T cells
Anti-cancer Therapies and the IR
Category Example Effect IR
Radiation γ / α BM ablation/ localised X
Alkylating Cyclo-phosphamide
DNA X-linking XAnti-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.