Objectives
- Immune suppression → cancer
- Inflammation → Cancer
- Cancer → immune suppression
- Chemotherapy and immune activation by “Immunogenic tumour cell death”
- Immune Modulation Cancer vaccines and adoptive t cell therapy
Origins of cancer
The origin of cancers can be from a few places:
- Genetic mutations on to oncogenes
- Viral Concogenes or genome integration
- Immune suppression leading to body being unable to clear cancer (transplant patients)
- Chronic inflammation (sets up a nice microenvironment)
Cancer in transplant patients
Immunosuppressants suppress T cells and NK cells Incidence of viral and spontaneous cancers higher in immunosuppressed frouped as a result Solid cancers higher in transplant patients than in noraml population
Cancer arising from chronic inflammation
Increase collular proliferation leads to more chances of mutati. DNA damage from various sources like Reactive oxygen species released from neutrophils
Inflammation leads to cancer by altering the tumour microenvironment
Mechanisms are unclear but inflammation likely results in a pro metastatic niche
Infilaraiton of tumour promoting fibroblasts suppressive macrophages and myeloid derived suppressor cells
Immune suppression caused by cancer
Neoplastic tissue is a darwinian microenvironment (Balkwill et al,)
Tunmour cells must evase cell cycle control and the immune system, and therefore cancers are often made of the “fittest” tumour cells. Suppression can be local (in tumour) and systemic (often late stage)
Tumour antigens
Tumnours both overexpress self antigens and also produce new ones (as they are genomically unstable)
- Neoantigens: tumour specific, result from mutations
- Tumour associated antigens: result from dysregulation of gene expression
Cancer can be recognised by the immune system
Tumour can be rapidly eliminated or may exist over months or years Usual outcomes
- Elimination (tumour destroyed)
- Equilibrium (destruction of tumour cells with low fitness)
- Escape (tumour evades the immune system and grows)
How to target cancer using the immune system
Chemotherapy induced cancer call death and awakens the immune system to fight cancer. Dying tumour cells can be immunogenic
Usually cell death is quiet and immunosuppressant but radiation and chemotherapy induced severe cellular stress
Chemo can also inhibit myeloid derived suppressor cells (MDSC)
This can make tumour cells immunogenic and break the cycle of immune suppression
Cancer immunotherapy
- cancer vaccines
- checkpoint inhibitors
- Chimeric antigen receptors
An example of a vaccine that reduced cancer is the HPV vaccines
Immunising patients with tumour antigens but targeting viral agents of oncogenesis is
Adoptive T cell transfer
TIL
Culture T cells from inside tumours and give them hyping up chemicals reinject them also block molecules that c=induce T cell exhaustion (CTLA-4 and PD-1)
Slow to act be work even after drug withdrawal
Tumour specific CAR T cells into patients
Chimeric antigen receptor composed of an anticancer antigen antibody (B cell derived) and T cells signalling componenets
Patients T cells are transduced usinf retrovirus containing the CAR
Car is b cell derived and works well