@article{656b3f7ff716462eb1fffe650e8a58f8,
title = "The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling",
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.",
keywords = "ER stress, MDSCs, NRF2, PERK, STING, tumor immunity, type I IFN, unfolded protein responses",
author = "Eslam Mohamed and Sierra, {Rosa A.} and Jimena Trillo-Tinoco and Yu Cao and Patrick Innamarato and Payne, {Kyle K.} and {de Mingo Pulido}, Alvaro and Jessica Mandula and Shuzhong Zhang and Paul Thevenot and Subir Biswas and Abdalla, {Sarah K.} and Costich, {Tara Lee} and Kay H{\"a}nggi and Anadon, {Carmen M.} and Flores, {Elsa R.} and Haura, {Eric B.} and Shikhar Mehrotra and Shari Pilon-Thomas and Brian Ruffell and Munn, {David H.} and Cubillos-Ruiz, {Juan R.} and Conejo-Garcia, {Jose R.} and Rodriguez, {Paulo C.}",
note = "Funding Information: We thank the Flow Cytometry Core, the Tissue Imaging Core, and the Analytic Microscopy Core, all from Moffitt Cancer Center and partially funded through CCSG-CA076292. We also thank J. Francis from the Lung Data Service at Moffitt. This study was supported in part by NIH grants R01CA184185 and R01CA233512 (to P.C.R.); R01CA103320 and R01CA211229 (to D.H.M.); and R01CA157664, R01CA124515, and R01CA178687 (to J.R.C.-G.). J.R.C.-R. was supported by Department of Defense (DOD) Ovarian Cancer Academy grant W81XWH-16-1-0438, the Mark Foundation ASPIRE Award, the Pershing Square Sohn Cancer Research Alliance, and the Stand Up to Cancer Phillip A. Sharp Award. E.M. and P.C.R. planned, designed, developed, and analyzed experiments; supervised the study; and wrote the manuscript. E.M. R.A.S. J.T.-T. Y.C. P.I. K.K.P. A.d.M.P. J.M. S.Z. P.T. S.B. S.K.A. T.L.C. K.H. and C.M.A. developed methodologies, performed experiments, and acquired data. E.R.F. E.B.H. S.M. S.P.-T. B.R. D.H.M. J.R.C.-R. and J.R.C.-G. provided reagents and advice for experiments. All authors revised and approved the manuscript. The authors declare no competing interests. Funding Information: We thank the Flow Cytometry Core, the Tissue Imaging Core, and the Analytic Microscopy Core, all from Moffitt Cancer Center and partially funded through CCSG-CA076292. We also thank J. Francis from the Lung Data Service at Moffitt. This study was supported in part by NIH grants R01CA184185 and R01CA233512 (to P.C.R.); R01CA103320 and R01CA211229 (to D.H.M.); and R01CA157664 , R01CA124515 , and R01CA178687 (to J.R.C.-G.). J.R.C.-R. was supported by Department of Defense (DOD) Ovarian Cancer Academy grant W81XWH-16-1-0438 , the Mark Foundation ASPIRE Award, the Pershing Square Sohn Cancer Research Alliance , and the Stand Up to Cancer Phillip A. Sharp Award. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "14",
doi = "10.1016/j.immuni.2020.03.004",
language = "English (US)",
volume = "52",
pages = "668--682.e7",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "4",
}
