Cytotoxicity, cell death and cancer immunotherapy
3 important questions on Cytotoxicity, cell death and cancer immunotherapy
How do CD8 T cells kill their targets cells?
CD8 T cells kill by inducing their targets to undergo apoptosis.
Apoptosis can be induced by two ways:
Effector caspase 3,6,7 that cleave proteins involved in cellular integrity and also activate enzyme that promote apoptosis
- specific recognition of peptide:MHC complex and CTL bind to virus-infected cell
- CTL programs target for death, inducing DNA fragmentation
- CTL migrates to new target
Apoptosis can be induced by two ways:
- Extrinsic pathway
- activation of death receptors by extracellulaire ligands
- initiator caspase 8 and 10
- intrinsic pathway
- in respons to noxious stimuli or lack of growth factor for survival
- initiator caspase 9
Effector caspase 3,6,7 that cleave proteins involved in cellular integrity and also activate enzyme that promote apoptosis
Mechanism of tumor to avoid immune
- Low immunogenicity; no peptide:MHC ligand, no co-stimulatry molecules
- Tumor treated as self-antigen
- tumor antigens taken up and presented by APCs in absence of co-stimulation tolerize T cells
- antigenic modulation tumor do no express antigens for T cell recogination by lack go MHC
- tumors that lose one MHC molecule might avoid CD8 and still remaining resistant to NK
- tumor-induced immune suppression
- PD-1L inhibit immune respons
- IDO supress local Imme response
- Tumor-induced privileged site
- factors secreted by tumors create physical barrier to immune system
- TGF-b supress inflammatory T respons and cell-mediated immunity
- MDSCs inhibit T cell activation
Reason why vaccine against cancer is difficult
- Neoantigens are not the same in different patient tumor
- suitability of epitopes would depend on the patient MHC alleles
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