Authors: Mohamed, Eslam; Sierra, Rosa A.; Trillo-Tinoco, Jimena; Cao, Yu; Innamarato, Patrick; Payne, Kyle K.; de Mingo Pulido, Alvaro; Mandula, Jessica; Zhang, Shuzhong; Thevenot, Paul; Biswas, Subir; Abdalla, Sarah K.; Costich, Tara Lee; HÃ¤nggi, Kay; Anadon, Carmen M.; Flores, Elsa R.; Haura, Eric B.; Mehrotra, Shikhar; Pilon-Thomas, Shari; Ruffell, Brian; Munn, David H.; Cubillos-Ruiz, Juan R.; Conejo-Garcia, Jose R.; Rodriguez, Paulo C.
Issue: Immunity. 2020 Apr 14;52(4):668-682.e7.
The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8+ T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy. Keywords: ER stress; MDSCs; NRF2; PERK; STING; tumor immunity; type I IFN; unfolded protein responses.