Abstract B035: The contribution of inflammasomes and cGAS-STING in RT-induced cell fate

Abstract

Abstract Radiotherapy (RT) is a curative treatment modality for many solid cancers. Our group has previously demonstrated that activation of the cGAS-STING pathway by RT induces inflammatory cytokine production and subsequent stimulation of anti-tumour immunity in concert with immune checkpoint blockade treatment. We have identified three other proteins that contribute to inflammatory signalling after RT: AIM2 (Absent in Melanoma 2), NLRP3 (NOD-Like Receptor Pyrin Domain-Containing 3), and IFI16 (Interferon Gamma Inducible Protein 16). Each of these proteins contribute to form distinct protein complexes called inflammasomes that, like cGAS-STING, sense cytoplasmic DNA. Little is known about how inflammasome signalling may change after RT, or how inflammasomes may influence RT-ICB induced anti-tumour immunity. We hypothesize that RT induces inflammasome signalling to influence specific gene expression and cytokine profiles, in tandem with alterations in cellular fate with implications for systemic anti-tumour immunity triggered by radiotherapy. We will present ongoing work in which we show that pharmacological or genetic disruption of inflammasomes alters cytokine production post-RT. We also demonstrate that manipulation of cell fate through senolytic therapy or manipulation of caspase activity alters the balance of cytokine production post-RT. Together our data strongly implicates the role of several inflammasome complexes in the response of epithelial cells to RT. Our work will also highlight the possible crosstalk between the cGAS-STING pathway and inflammasome complex pathway, both triggered by RT. Understanding and subsequent manipulation of cell fate, in part through inflammasome and cGAS-STING mediated activity, may be a therapeutic strategy to influence treatment responses, such as anti-tumour immunity, in cancer. Citation Format: Cindy T Ha, Shirony Nicholson-Puthenveedu, Shane M Harding. The contribution of inflammasomes and cGAS-STING in RT-induced cell fate [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B035.