ER stress upregulates the unfolded protein response to promote cell survival. Mandula et al. assessed the immune consequences of blocking that protective response by modulating PERK. Genetic or pharmacological blockade of PERK led to paraptosis, a form of cell death characterized by dysregulated protein turnover, with release of immunogenic cell death (ICD) signals ATP and HMBG1, which promoted expansion and activation of monocyte-derived inflammatory DCs. PERK ablation in implanted and spontaneous tumor models led to improved local and abscopal tumor control. Gene signatures for both PERK and ICD correlated with overall survival in TCGA melanoma data.
Contributed by Ed Fritsch
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 SEC61_-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.
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (2) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (3) California N
Author Info: (1) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (2) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (3) California Northstate University, Elk Grove, CA 95757, USA. (4) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (5) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (6) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (7) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (8) Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (9) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (10) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (11) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (12) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (13) Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (14) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (15) Department of NeuroOncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (16) Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA. (17) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (18) Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA. (19) Department of Pediatrics, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA. (20) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (21) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. (22) Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address: Paulo.Rodriguez@Moffitt.org.
