Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses

Cancer Cell. 2022 Oct 10;40(10):1145-1160.e9. doi: 10.1016/j.ccell.2022.08.016. Epub 2022 Sep 22.

Abstract

Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.

Keywords: PERK; immunogenic cell death; tumor immunity; type I IFN; unfolded protein responses.

Publication types

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

MeSH terms

  • Animals
  • Endoplasmic Reticulum Stress
  • Interferon Type I* / metabolism
  • Mice
  • Neoplasms*
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • Unfolded Protein Response
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Interferon Type I
  • eIF-2 Kinase