Withdrawn 31st Lorne Cancer Conference 2019

Tumor immune evasion arises through loss of TNF sensitivity     (#108)

Jane Oliaro 1 , Conor J Kearney 1 , Stephin J Vervoort 1 , John Silke 2 , Ricky W Johnstone 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Water and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

Immunotherapies that enhance cytotoxic T cell activity against tumour cells have revolutionised outcomes for cancer patients. However, patient responses vary widely, and so there is considerable interest in understanding how tumours evade this form of therapy. To investigate this, we carried out a series of CRISPR screens to identify mechanisms of tumour immune evasion from T cell killing. We found that deletion of key genes within the TNF signalling, IFN-gamma signalling, and antigen presentation pathways provided protection of tumour cells from T cell killing, and blunted anti-tumour immune responses in vivo. Our results also highlighted a role for TNF-mediated bystander killing as a potent T cell effector mechanism that can be enhanced by a class of drugs, called smac-mimetics, that inhibit IAPs and can sensitise tumour cells to TNF-induced cell death. Indeed, our studies showed that the smac-mimetic, birinapant, significantly enhanced tumour cell death in the presence of T cells; an effect that can be amplified upon checkpoint blockade. Taken together, we identify T cell-derived TNF as a potent anti-tumour effector mechanism that can be enhanced with birinapant, and an opportunity for combination therapy through co-inhibition of immune checkpoints.