Melissa A Johnson, Siva Karthik Varanasi, Kailash Chandra Mangalhara, Kathryn Lande, Gladys R Rojas, Pau B Esparza-Moltó, Mack B Reynolds, Neva Olliffe, Karl Wessendorf-Rodriguez, Sagnika Ghosh, Dan Chen, Alexandra G Moyzis, Matthew P Donnelly, Rebecca Chinn, Ziyan Xu, Kym J Grae, Victoria Tripple, Michael A LaPorta, Christian M Metallo, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel
Interferons (IFNs) are proinflammatory cytokines that promote immune cell engagement to eliminate malignant cells. Paradoxically, chronic interferon signaling can also activate anti-inflammatory mechanisms that allow cancer cells to evade the immune system. In this study, we sought to determine the cellular mechanisms underlying this switch from antitumorigenic to protumorigenic interferon activity. We show that chronic type II interferon (IFN-II) exposure distinctively induced tumor growth by activating a type I interferon (IFN-I) response mediated by release of double-stranded mitochondrial RNA (ds-mtRNA) into the cytoplasm. This IFN-I signal synergized with IFN-II to enhance tumor growth by increasing immunosuppressive prostaglandin E2 (PGE2) synthesis through increased cyclooxygenase 2 expression. Elimination of PGE2 synthesis in immunotherapy-resistant melanoma cells restored their responsiveness to anti-PD1 treatment, indicating that this covert mtRNA-IFN-prostaglandin pathway could be a therapeutic target to combat immunotherapy resistance.