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Mandula, Jessica K.; Chang, Shiun; Mohamed, Eslam; Jimenez, Rachel; Sierra-Mondragon, Rosa A.; Chang, Darwin C.; Obermayer, Alyssa N.; Moran-Segura, Carlos M.; Das, Satyajit; Vazquez-Martinez, Julio A.; Prieto, Karol; Chen, Ann; Smalley, Keiran S.M.; Czerniecki, Brian; Forsyth, Peter; Koya, Richard C.; Ruffell, Brian; Cubillos-Ruiz, Juan R.; Munn, David H.; Shaw, Timothy I.; Conejo-Garcia, Jose R.; Rodriguez, Paulo C.
Cancer cell, 10/2022, Letnik: 40, Številka: 10Journal Article
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. Display omitted •Kinase PERK in melanoma cells restricts protective tumor-specific T cell immunity•PERK targeting drives immunogenic melanoma cell death via SEC61β-linked paraptosis•PERK-null tumors promote the expansion of immune competent monocyte-derived DCs•Stroma-originated type I IFN reprograms myelopoiesis in PERK-null tumors via STAT1 How adaptation to endoplasmic reticulum (ER) stress in cancer cells modulates anti-tumor immunity remains elusive. Mandula et al. demonstrate that elimination of the ER stress-related kinase, PERK, in melanoma cells activates protective T cell responses through paraptosis-mediated immunogenic cell death, which primes expansion of monocytic-lineage inflammatory DCs via type-I IFN-STAT1.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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