Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer

• Type of Material: Article
• Authors: Brian P Riesenberg, University of North Carolina Chapel Hill; Elizabeth G Hunt, University of North Carolina Chapel Hill; Megan D Tennant, Medical University of South Carolina; Katie E Hurst, University of North Carolina Chapel Hill; Alex M Andrews, Medical University of South Carolina; Lee R Leddy, Medical University of South Carolina; David M Neskey, Medical University of South Carolina; Elizabeth G Hill, Medical University of South Carolina; Guillermo OR Rivera, Medical University of South Carolina; Chrystal Paulos, Emory University; Peng Gao, North western Univ; Jessica E Thaxton, University of North Carolina Chapel Hill
• Language: English
• Date: 2022-12-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-22-1744
• Title of Journal or Parent Work: CANCER RESEARCH
• Volume: 82
• Issue: 23
• Start Page: 4386
• End Page: 4399
• Grant/Funding Information: R01CA244361-01A1, R01CA248359-01 (JET), T32 5T32AI132164-04 (BPR), T32 DE01755 (MDT), T32 CA 193201 (AMA), P30 CA138313 (EGH)
• Keywords: TUMOR MICROENVIRONMENT; PROTEASOME ACTIVITY; MEMORY; Oncology; Science & Technology; UNFOLDED PROTEIN RESPONSE; SURVIVAL; SERINE 51; EIF2-ALPHA; Life Sciences & Biomedicine; ACTIVATION; PHOSPHORYLATION; METABOLISM

Abstract

Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.