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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • 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
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunosuppression Therapy
  • Interferon-alpha / genetics
  • Interferon-alpha / immunology
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Male
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Myeloid-Derived Suppressor Cells / immunology
  • Myeloid-Derived Suppressor Cells / pathology
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / immunology
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Unfolded Protein Response / immunology
  • eIF-2 Kinase / deficiency
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology*

Substances

  • Interferon-alpha
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Receptors, Interferon
  • Sting1 protein, mouse
  • Interferon-beta
  • PERK kinase
  • eIF-2 Kinase