Dr Jane Oliaro obtained her BSc (Hons) degree from Monash University in Melbourne and PhD from Massey University in New Zealand, followed by an INSERM postdoctoral fellowship in Montpellier, France. 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. Jane has been the recipient of multiple NHMRC project grants, one of which was included in the NHMRC 'Ten of the Best Research Projects' for 2010 and an NHMRC fellowship. She was also awarded a NHMRC Inaugural Achievement Award for her research on T cell polarity proteins and asymmetric T cell division. Her laboratory focuses on the regulation of cytotoxic lymphocyte-tumour cell interactions, and therapies that enhance anti-tumour immunity.
TNF in anti-tumour immunity and resistance to immunotherapy
Immunotherapies that enhance cytotoxic T cell activity against tumour cells have revolutionised outcomes for cancer patients. However patient responses vary widely, 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 was amplified upon checkpoint blockade. Furthermore, birinapant significantly enhanced CAR T cell therapy in a solid tumour setting. 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.