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

• Published in: Immunity (Cambridge, Mass.) Vol. 52; no. 4; pp. 668 - 682.e7
• Main 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, Hänggi, 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.04.2020; Elsevier Limited
• Subjects: Ablation; Activation; Animals; Antigens; Antioxidants; Cancer; Cancer immunotherapy; Carcinoma, Lewis Lung - genetics; Carcinoma, Lewis Lung - immunology; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - immunology; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell growth; Cell-mediated immunity; Cytokines; Deletion; eIF-2 Kinase - deficiency; eIF-2 Kinase - genetics; eIF-2 Kinase - immunology; Endoplasmic reticulum; ER stress; Female; Gene expression; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Immunity; Immunoregulation; Immunosuppression; Immunotherapy; Interferon; Interferon-alpha - genetics; Interferon-alpha - immunology; Interferon-beta - genetics; Interferon-beta - immunology; Kinases; Lymphocytes; Lymphocytes T; Male; MDSCs; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Metastases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - immunology; Mitochondria - metabolism; Mitochondrial DNA; Myeloid cells; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - pathology; Myelopoiesis; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - immunology; NRF2; PERK; Phosphorylation; Protein folding; Proteins; Receptors, Interferon - genetics; Receptors, Interferon - immunology; Signal Transduction; Signaling; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; STING; Suppressor cells; Transcription factors; tumor immunity; Tumors; type I IFN; Unfolded Protein Response - immunology; unfolded protein responses; MDSCs; NRF2; unfolded protein responses; ER stress; STING; tumor immunity; PERK; type I IFN
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.03.004

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. [Display omitted] •Tumor-infiltrating MDSCs demonstrate increased activation of PERK signaling•PERK ablation in MDSCs elicits anti-tumor T cells and synergizes with immunotherapy•Deletion of PERK reprograms tumor MDSC functionality by blunting NRF2 signaling•Reduced NRF2 primes STING-to-type I IFN axis in PERK-null MDSCs via cytosolic mtDNA The mechanisms underlying the augmented immunoinhibitory activity of myeloid-derived suppressor cells (MDSCs) upon infiltration into tumors remain elusive. Mohamed and colleagues demonstrate that the unfolded protein response (UPR)-related kinase PERK promotes tumor MDSC functionality through stimulation of the transcriptional factor NRF2, which restricts the immunostimulatory axis of cytosolic mitochondrial DNA-STING-type I IFN.