Lecture 10 (immunotherapies) Flashcards
How can the immune system contribute to the anti-tumour response
- By destroying viruses that are known to transform cells
- By eliminating pathogens to reduce pro-tumour inflammation as 20% of cancers are now thought to be associated with microbial infection
- By identifying and destroying cancerous cells which is mediated by immune ‘killer’ cells
A bad tumour immune profile is composed of what cells
-M2 macrophages
-myeloid derived suppressor cells (MDSCs)
-Th2 cells
-Treg cells (prevent immune cells from killing cancer cells)
A good tumour immune profile is composed of what cells
-cross-presenting APCs
-NK cells
-Th1 (which is more beneficial than Th2)
-CD8+ CTL response
9 tumour escape mechanisms
- loss of Tumour Antigen
- loss of MHC I or NKG2D
- loss of IFNg responsiveness (pathway defects)
- inhibition of DC maturation/function
- loss of costimulatory molecules such as increasing CTLA4
- increase Treg activity which dampens down other T cells
- MDSC
- immunomodulatory molecules such as IL10 which dampens immune response
- cancer cells use checkpoints to dampen the immune response
Two classes of tumour antigens
Tumour-specific antigens and tumour-associated antigens
Tumour specific antigens
-Only occur in neoplastic (tumor) cells.
-They are recognised as non-self by CD8+ CTLs
Examples of TSA:
-Mutated cellular proteins which leads to APC expression of novel peptides presented by MHC class I
-Virally derived antigens such as HPV E6 and E7 proteins which are found in 80% of invasive cervical cancers
Tumour associated antigens
Are normal cellular proteins with unique expression patterns, they are only expressed at specific sites or stages of development (eg. foetal) or at low levels in normal cells.
-Reexpression of foetal or embryonic genes are called oncofoetal tumour antigens eg. CEA (carcinoembryonic antigen)
-90% of all patients with advanced CRC have increased CEA in their serum
-May also be oncogenes that are expressed at abnormally high levels such as EGFR and HER2
What is the anti-tumour response shown by NK cells (innate immune cells)
-NK cells kill tumour cells by:
1. Showing reduced MHC I expression which is detected by KIRs (killer cell immunoglobulin-like receptors),
2. By killing tumours that overexpress ligands for activating NK receptors
3. By IFNg secretion which stimulates CTL response
4. By being the key mediators of ADCC
NK deficient mice
Are known as SKID mice
-They have increased lymphomas/sarcomas
What is the anti-tumour response of macrophages M1 (innate immune cells)
-IFNg drives the M1 phenotype ADCC and secrete cytokines (TNFalpha, IL-12, IL23) which exert cytotoxic activity on tumour cells
-High MHC class II/costimulatory molecules (APCs) secrete chemokines that lead to Th1, CTL recruitment, and NK cells
What is the anti-tumour response of T cells
-T cells have strong anti-tumour CTL (CD8+) activity which correlates with tumour remission and maintains state of immune mediated neoplastic cell dormancy
-Th1 cells secrete IFNg which promotes M1 macrophage response and increases MHC I expression which facilitates CTL recognition of tumour antigens
-Th17 cells secret IL17 which leads to secretion of pro-angiogenic factors
-TILs are a prognostic indicator
Anti-tumour response of B cells
-B cells can secrete anti-tumour antibodies
-ADCC by NK cells and macrophages
-Bad effect is that B cells can block CTL response by masking tumour antigens
-Also tumour cells can evade B cells by chopping them up and excreting them.
How can cancer evade the immune system
1- active immunosuppression in tumour environment
2- chronic inflammation
3- evasion of immune recognition and activation
4- tumour cell avoidance of apoptotic signals
5- poor co-stimulatory signals provided by tumour cells
6- expression of co-inhibitory molecules
What are the details of 1- active immunosuppression in tumour environment
-Dampening of immune response by M2 macrophages, MDSCs, Tregs, and Th2 cells
-IL4 drives M2 phenotype which release immune dampening cytokine secretion IL10 chemokines which lead to Treg and Th2 recruitment, pro angiogenic factors (VEGF) and growth factors released by M2 macrophages
-NK cells can be defective at tumour site
-Neutrophils secrete VEGF and proteinases elastase and MMP8/9
-MDSCs are immature cells comprised of precursors of macrophages, granulocytes, DCs, and myeloid cells at earlier stages of differentiation
-Tumours secrete factors to promote MDSC expansion as they induce CD8+ T cell tolerance, block NK cytotoxicity, and polarise immunity (push towards pro-tumour rather than anti-tumour immune response, treatment giving to push this balance back)
what are the details of 2- chronic inflammation
-Increases cellular stress and genotoxic stress thereby increasing mutation rate
-Growth factors and cytokines released by leukocytes can also lead to tumour growth
-Inflammation is proangiogenic
-Iink between increased cancer risk and people with obesity as these people experience higher levels of chronic inflammation
