Lecture 11: Cancer and the Immune System Flashcards
Whate are the three protective mechanisms for supressing tumours by the immune system
- Protects against bacterial and viral infections that may be oncogenic
- Helps resolve inflammation which is a promoter of cancer
- Directly recognise and kill tumour cells
What is the tumour immunosurveillance hypothesis?
1909 (Ehrlich); refined in 1950s (by Burnet & Thomas)
Immune system constantly surveys newly developing tumours, and if effective, prevents development of neoplastic disease.
Assumed that clinically evident tumours were ones that had escaped the net
What is the evidence for immune surveillance?
Increased incidence of tumours in:
1. Immunosuppressed recipients after organ transplantation (malignant melanoma: 0.3% general paediatric popn., 4% paediatric transplants)
2. Patients with inborn or acquired defects of immune system
BUT
- immunosuppressed patients not at risk of increased epithelial malignancies
- No greater incidence in ‘immunoprivilidged sites’ (e.g., eye)
- Evidence against from nude mice studies
What is the evidence in animal modes for immune responses to tumours?
- 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
What are the innate mechanisms in immunosurveillance?
- Macrophages (TAMs: M1 and M2) and neutrophils (N1 and N2)
phagocytosis
antibody-dependent cellular cytotoxicity (ADCC)
secretion of tumour-growth inhibitory cytokine - NK cells
“missing self” hypothesis: decreased levels of MHC molecules on
tumour cell can be a trigger for NK activityRecognise MHC-I molecules, and cancer cells, via numerous receptors:
CD95/NKG2A, NKG2D, KIR (Killer inhibitory receptor), LIR/LIT
What is meant by complement?
Activation of complement in tumour tissue has been demonstrated
What are some different types of cytokines?
IFN-alpha, IFN-gamma, TNF, TRAIL, IL-12, etc
What are adaptive immune mechanisms in immunosurveillance?
1950s - unequivocal demonstration that tumour cells express antigens capable of eliciting specific and protective immunity
Each tumour carries unique set of antigens (tumour specific / associated antigens)
However: most genetic changes are immunologically silent
What is the cancer-immunity cycle?
the generation of immunity to cancer is a cyclic process that can be self propagating, leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T cell responses
What is the process of the cancer-immunity cycle?
- release of cancer cell antigens (cancer cell death)
- Cancer antigen presentation (dendritic cells/APCs)
- Priming and activation (APCs & T-cells)
- Trafficking of T-cells to tumours (CTLs)
- Infiltration of T-cells into tumours (CTLs, endothelial cells)
- Recognition of cancer cells by T-cells (CTLs, cancer cells)
- Killing of cancer cells (immune and cancer cells)
How is the cancer-immunity cycle controlled?
Each step of the cycle requires the coordination of numerous factors, both stimulatory an inhibitory in nature
Why are immune checkpoints in place?
Immune regulatory pathways normally a key part of tolerance mechanisms to avoid anti-self recognition
What is meant by TAA
“tumour associated antigen”
What is the importance of some molecules involved at immune checkpoints?
CTLA-4 = key negative regulator
PD-1 and PD-L1 (or L2) = other co-inhibitory molecules`
What antigens are involved in tumour recognition?
TUMOUR-SPECIFIC ANTIGENS
1. Bcr-abl (CML)
2. CDK-4 / beta-catenin (melanoma)
DIFFERENTATION ANTIGENS
1. Tyrosinase (TRP-1/2)
2. Melan-A (melanoma)
3. Monoclonal Ab (myeloma)
TESTES-SPECIFIC ANTIGENS
1. MAGE 1-3 (melanoma)
2. NY-ESO-1 (melanoma)
TUMOUR ASSOCIATED ANTIGENS
1. MUC-1 (myeloma etc)
2. alpha-fetoprotein (many)
3. Her-2/neu (breast)
4. WT-1 (many)
5. Myeloblastin (leukaemias)
6. Survivin (many)
