TMET-30. ONCOLYTIC HSV REWIRES METABOLISM TO PROMOTE ANTITUMOR IMMUNITY THROUGH REDUCTIVE CARBOXYLATION AND FERROPTOSIS

Abstract Cancer cells autonomously rewire metabolism to meet increased bioenergetic demands. Oncolytic HSVs (oHSVs) are attenuated Herpes simplex type 1 derived viruses that lyse tumor cells releasing damage-associated molecules triggering antitumor immunity. Currently one oHSV-1 derived virus is approved for melanoma treatment in the USA and another for recurrent GBM in Japan. While several other viruses are being evaluated in clinical trials for safety and efficacy, an understanding of the impact of oHSV therapy on cancer cell metabolism is largely unexplored. A detailed understanding of how oHSV impact tumor cell metabolism and oxidative stress is important to understand the unique susceptibilities that can further be exploited to improve the therapeutic index. Here, we analyzed transcriptomic changes in tumor biopsies of recurrent high-grade glioma patients treated with oHSV. RNA-seq data obtained from pre- and post-G207 treated biopsies from phase-Ib study patients (NCT00028158) revealed enrichment in pathways related to citric acid cycle, oxidative phosphorylation, and glutamate metabolism. We confirmed these changes by RNA sequencing of oHSV-infected patient derived GBM cells. Mechanistically, oHSV hijacked cellular glucose metabolism to increase oxidative phosphorylation and modulated cellular glutamine metabolism towards reductive carboxylation and reduced free glutathione, collectively contributing to increased ROS generation. Kinome profiling revealed PKC activation upon treatment with oHSV. Increased ROS combined with reduced glutathione, and PKC activation promoted ferroptotic cell death characterized by increased lipid peroxidation and smaller, ruptured mitochondria, and contributed to immunotherapy by this treatment. IDH mutant tumors that block reductive carboxylation were resistant to oHSV-induced ferroptotic cell death and did not benefit from oHSV-induced antitumor benefit. Together, this study presents avenues to enhance antitumor immunity by oHSV therapy.