The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors Through Inhibition of STING Signaling
Eslam Mohamed1, Rosa A Sierra1, Jimena Trillo-Tinoco2, Yu Cao1, Patrick Innamarato1, Kyle K Payne1, Alvaro de Mingo Pulido1, Jessica Mandula1, Shuzhong Zhang3, Paul Thevenot4, Subir Biswas1, Sarah K Abdalla1, Tara Lee Costich1, Kay Hänggi1, Carmen M Anadon1, Elsa R Flores5, Eric B Haura5, Shikhar Mehrotra6, Shari Pilon-Thomas1, Brian Ruffell1, David H Munn7, Juan R Cubillos-Ruiz8, Jose R Conejo-Garcia1, Paulo C Rodriguez9
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
- Bristol-Myers Squibb, Devens, MA 01434, USA.
- Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH 43205, USA.
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
- Department of Pediatrics, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: Paulo.Rodriguez@Moffitt.org.
Abstract
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.
Presented By Jessica Mandula