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

Eslam Mohamed, Rosa A. Sierra, Jimena Trillo-Tinoco, Yu Cao, Patrick Innamarato, Kyle K. Payne, Alvaro de Mingo Pulido, Jessica Mandula, Shuzhong Zhang, Paul Thevenot, Subir Biswas, Sarah K. Abdalla, Tara Lee Costich, Kay Hänggi, Carmen M. Anadon, Elsa R. Flores, Eric B. Haura, Shikhar Mehrotra, Shari Pilon-Thomas, Brian RuffellDavid H. Munn, Juan R. Cubillos-Ruiz, Jose R. Conejo-Garcia, Paulo C. Rodriguez

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)668-682.e7
JournalImmunity
Volume52
Issue number4
DOIs
StatePublished - Apr 14 2020

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Keywords

  • ER stress
  • MDSCs
  • NRF2
  • PERK
  • STING
  • tumor immunity
  • type I IFN
  • unfolded protein responses

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Mohamed, E., Sierra, R. A., Trillo-Tinoco, J., Cao, Y., Innamarato, P., Payne, K. K., de Mingo Pulido, A., Mandula, J., Zhang, S., Thevenot, P., Biswas, S., Abdalla, S. K., Costich, T. L., Hänggi, K., Anadon, C. M., Flores, E. R., Haura, E. B., Mehrotra, S., Pilon-Thomas, S., ... Rodriguez, P. C. (2020). The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling. Immunity, 52(4), 668-682.e7. https://doi.org/10.1016/j.immuni.2020.03.004