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The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors Through Inhibition of STING Signaling

Immunity. 2020 Apr 14;52(4):668-682.e7. doi: 10.1016/j.immuni.2020.03.004. | PubMed

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

  1. Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  2. Bristol-Myers Squibb, Devens, MA 01434, USA.
  3. Center for Microbial Pathogenesis, Nationwide Children's Hospital, Columbus, OH 43205, USA.
  4. Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
  5. Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  6. Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
  7. Department of Pediatrics, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
  8. 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.
  9. 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