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

Publication ,  Journal Article
Mandula, JK; Chang, S; Mohamed, E; Jimenez, R; Sierra-Mondragon, RA; Chang, DC; Obermayer, AN; Moran-Segura, CM; Das, S; Vazquez-Martinez, JA ...
Published in: Cancer Cell
October 10, 2022

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.

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Published In

Cancer Cell

DOI

EISSN

1878-3686

Publication Date

October 10, 2022

Volume

40

Issue

10

Start / End Page

1145 / 1160.e9

Location

United States

Related Subject Headings

  • eIF-2 Kinase
  • Unfolded Protein Response
  • T-Lymphocytes
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice
  • Interferon Type I
  • Endoplasmic Reticulum Stress
  • Animals
 

Citation

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Mandula, J. K., Chang, S., Mohamed, E., Jimenez, R., Sierra-Mondragon, R. A., Chang, D. C., … Rodriguez, P. C. (2022). Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses. Cancer Cell, 40(10), 1145-1160.e9. https://doi.org/10.1016/j.ccell.2022.08.016
Mandula, Jessica K., Shiun Chang, Eslam Mohamed, Rachel Jimenez, Rosa A. Sierra-Mondragon, Darwin C. Chang, Alyssa N. Obermayer, et al. “Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.Cancer Cell 40, no. 10 (October 10, 2022): 1145-1160.e9. https://doi.org/10.1016/j.ccell.2022.08.016.
Mandula JK, Chang S, Mohamed E, Jimenez R, Sierra-Mondragon RA, Chang DC, et al. 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.
Mandula, Jessica K., et al. “Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.Cancer Cell, vol. 40, no. 10, Oct. 2022, pp. 1145-1160.e9. Pubmed, doi:10.1016/j.ccell.2022.08.016.
Mandula JK, Chang S, Mohamed E, Jimenez R, Sierra-Mondragon RA, Chang DC, Obermayer AN, Moran-Segura CM, Das S, Vazquez-Martinez JA, Prieto K, Chen A, Smalley KSM, Czerniecki B, Forsyth P, Koya RC, Ruffell B, Cubillos-Ruiz JR, Munn DH, Shaw TI, Conejo-Garcia JR, Rodriguez PC. 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.
Journal cover image

Published In

Cancer Cell

DOI

EISSN

1878-3686

Publication Date

October 10, 2022

Volume

40

Issue

10

Start / End Page

1145 / 1160.e9

Location

United States

Related Subject Headings

  • eIF-2 Kinase
  • Unfolded Protein Response
  • T-Lymphocytes
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice
  • Interferon Type I
  • Endoplasmic Reticulum Stress
  • Animals