Studying the impact of programmed cancer cell death pathways on Type I interferons-based immunotherapy

Type I interferon (IFN) cytokines i.e. IFNα/β are potent defensive factors produced by our immune system to stop microbial infections. Due to their broad immunological activity, IFNα/β also have vital roles in sterile inflammatory diseases like cancer. Type I IFNs have diverse anticancer properties capable of causing tumour regression. These anticancer effects have driven the clinical prioritization of immunotherapies consisting of, or directly promoting, IFNα/β. However, IFNα/β immunotherapy has performed disappointingly in the clinic; but, beyond dose-related toxicity, most mechanisms modulating this performance remain unclear. We believe programmed cancer cell death might be one such mechanism. There is a high likelihood for interactions between Type I IFNs and cancer cell death, because IFNα/β directly induce it, and are combined with other cell death inducers in clinical setting. The problem is, despite this strong likelihood of interaction, extremely scanty knowledge exists on direct effects of the two major programmed cancer cell death pathways i.e. necroptosis & apoptosis, on Type I IFNs. We hypothesize that apoptosis or necroptosis in cancer cells may directly modulate IFNα/β levels, such that, depending on whether they maintain or decrease them, the potency of IFNα/β-driven immunity may vary. Hence, in this project we seek to understand the impact of apoptotic or necroptotic cancer cells on IFNα/β, and the influence of this interaction on anticancer immunity.