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-amma signalling, and antigen presentation pathways provided protection of tumour cells from T cell killing, and blunted anti-tumour immune responses in vivo. Importantly, the same immune evasion mechanisms were found upon screening with perforin deficient T cells, suggesting tumours evade the immune system by dampening the effects of cytokines, not direct killing via perforin. Indeed, we demonstrated that TNF-mediated bystander killing is a potent T cell effector mechanism capable of killing antigen-negative tumour cells. A new class of drugs, called smac-mimetics, are promising anti-cancer agents that can sensitise tumour cells to TNF-induced cell death. We found that T cells potently kill tumour cells in the presence of the smac-mimetic, birinapant, which sensitises the tumour cells to TNF secreted by the T cells upon antigen recognition. Importantly, the intrinsic perforin/granzyme route to T cell-mediated tumour cell killing was dispensable for the efficacy of birinapant, again emphasising the importance of the TNF-mediated extrinsic cell death pathway. In addition, the elevated levels of TNF produced by T cells upon checkpoint inhibition (e.g. PD-1 blockade) further enhanced tumour cell killing when combined with birinapant.
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.
Dr Jane Oliaro is a cellular immunologist specialising in cytotoxic lymphocytes and anti-tumour immunity. Following her undergraduate BSc (Hons) degree at Monash University in Melbourne, Jane undertook her PhD studies at Massey University in New Zealand. Her thesis focused on identifying immunogenic proteins of Helicobacter pylori for use in a vaccine. This was followed by an INSERM postdoctoral fellowship in Montpellier, France, where she studied the role of gamma-delta T cells in the clearance of Brucella-infected macrophages. She returned to her hometown Melbourne to undertake postdoctoral work at the Peter MacCallum Cancer Centre and in 2015 became Head of the Immune Defence Laboratory at the Peter Mac. Her laboratory focuses on the regulation of cytotoxic lymphocyte-tumour cell interactions, and therapies that enhance anti-tumour immunity.
Jane has been the recipient of an NHMRC fellowship and multiple NHMRC project grants, one of which was included in the NHMRC ‘Ten of the Best Research Projects’ for 2010. She was also awarded a NHMRC Inaugural Achievement Award for her research on T cell polarity proteins and asymmetric T cell division. Jane has served on both grant review and fellowship panels for the NHMRC for the past seven years and is actively involved in communicating research to the public through talks and fundraising events such as the Ride to Conquer Cancer.