Chronic type II interferon promotes tumor growth through mitochondrial RNA-induced type I interferon and prostaglandin synthesis

Abstract

Interferons are pro-inflammatory 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. Here, we sought to determine the cellular mechanisms underlying this switch from anti-tumorigenic to pro-tumorigenic interferon activity. We show that chronic type II interferon (IFN-II) uniquely 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 via increased cyclooxygenase 2 (COX2) 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.