Week 13 Part 2 - Cancer Immunology Flashcards
Most Common Cancers in Men
Prostate cancer > lung cancer > colon, rectum
Most Common Cancers in Women
Breast cancer > lung, colorectal > uterine cancer
What Causes Cancer
DNA is exposed to radiation, chemicals, viruses, part of aging process
DNA breaks and recombines incorrectly or mutates
Cell produces
- unusually large amounts of normal proteins
- an altered form of that protein
- no protein
Tumour Specific Antigens
Antigens (over)expressed by the tumour
Can lead to anti-tumour immunity
Tumour antigens can be used for:
- diagnosis
- targets for immunotherapies
Evidence of Cancer from Organ Transplants
Transplant patients - higher rate of cancer than general public
Melanoma - 0.3% general paediatric pop. versus 4% in paediatric transplants
Sarcoma - 3-fold higher risk in transplant patients
Lung carcinoma - 25-fold increase in cardiac transplant patients
Evidence that the Immune System can Destroy Tumour Cells
Some tumours spontaneously regress
Better prognosis if tumour infiltrating lymphocytes present
Tumours employ escape mechanisms to avoid immune destruction
Cytotoxic T cells & NK can kill tumour cells
Generating an Anti-Tumour Response
- Cell has mutated and is uncontrollably dividing taking over the tissue site
- DCs take up tumour cell and travel to lymph node
- Presents to naive T cell that has to have specific TCR
- Activation/production of tumour specific T cells which travel back to tumour tissue
CD8+ Cytotoxic T Cells - Role in Tumour Regression
Lyse cells expressing a specific antigen presented in MHC class I molecules
Release perforin, granzyme and FAS-FAS Ligand interactions
Why is the Immune Response to Tumours
Ineffective?
Tumour antigen/s are never presented to T cells
- ignorance
Tumour antigens are presented to T cells but:
- T cells are unresponsive (anergised/tolerised)
- the response is inappropriate - too little, too late
- T cells are induced to die (apoptosis)
- T cell (subsets) are unable to enter the tumour
- T cell responses are limited to a single epitope
- T cells express checkpoint molecules and/or their ligands
- tumour cells and infiltrating innate cells express checkpoint molecules and/or their ligands which can shut down T cells
Evading the Immune Response - Immunosuppresion
Tumour cells secrete suppressive cytokines e.g. TGFb, VEGF
Regulatory cells secrete suppressive cytokines e.g. TGFb, IL-10
- CD4+CD25+FOXP3+ T regulatory cells
- M2 macrophages
- myeloid-derived suppressor cells
Evading the immune response
‘Hide’ -> No MHC class I = cannot be a CTL target
No danger signal
- tumour cells do not initiate inflammation - e.g. no TLR activation
- tumour cells can present antigen - but no co-stimulation molecules
Three E’s of Cancer Immunoediting
Elimination
Equilibrium
Escape
Tumour Elimination
Innate cells recognise tumour establishment
Dendritic cells transport tumour antigen to LN
Tumour-specific T cells home to tumour site
Eliminate tumour cells
Tumour Equilibrium
Tumour-specific T cells home to tumour
Cannot completely eliminate tumour cells
Tumour cells avoid killing by genetic alteration
- lose tumour antigen
- downregulate MHC class I molecules
- secrete soluble factors that disable the immune system
- recruit regulatory cells into the tumour microenvironment
Current Therapies
Surgery - aims to remove the cancer
Chemotherapy and radiation - aims to directly kill cancer cells
Can be successful if cancer caught early enough
- but recurrences often occur after 5 years
- can have severe side effects
Cancer Immunotherapy
Aims to bolster the immune system so that it kills cancer cells
Cytokine Therapy - Interferons IFNa, IFNb, IFNg
Stimulate NK, T cells & macrophages
IFNg limits “Hairy” cell leukemia’s
Cytokine Therapy - Tumour Necrosis Factor
Directly attacks & kills tumour cells
Tested alone & in conjunction with IFNg
Cytokine Therapy - IL-2
Promotes CTL, NK & macrophages
Toxic
Effective -> melanoma, renal cancer
Cancer Vaccines
Based on tumour antigens
Aims to stimulate an immune response to a specific type of cancer:
- used to treat cancer patients
- may be used to prevent cancers developing
Tumour Cell-Based Vaccines
Injection with (usually irradiated)
- autologous tumour, from surgical resection or biopsy specimens
- allogeneic tumour from cell lines
Tumour cells modified => more immunogenic
- transduced with genes expressing cytokines or co-stimulatory molecules
Responses disappointing
Adoptive Transfer of Tumour-Specific Cytotoxic T Cells
Viruses used to insert genetically engineered genes into T cells
Genes code for antibodies that target a tumour antigen (antigen receptor)
T cell expressing the chimeric antigen receptor (CAR) on their surface are expanded
CAR T cells transferred back into the patient identify and destroy cancer cells
Dendritic Cell Vaccines
Blood & bone marrow DC readily accessible
Can generate large numbers in vitro
Can manipulate in vitro
- expose to tumour antigens
- genetically modify
- activate
Returned to host
Stimulate anti-tumour effector CTL
Pros and Cons of DC Vaccines
Feasible & safe
BUT tolerance occurred when immature DC given to patients
Clinical responses in 10-20% of patients (more common in melanoma)
Anti-Tumour Antibodies - Monoclonal Antibodies
Developed over the last 30 years
Highly specific
Target tumour antigens
Can be mass produced
