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.
Original language | English (US) |
---|---|
Pages (from-to) | 4386-4399 |
Number of pages | 14 |
Journal | Cancer Research |
Volume | 82 |
Issue number | 23 |
DOIs | |
State | Published - Dec 1 2022 |
Funding
The authors thank Dr. Zihai Li for continued mentorship over the course of development of this manuscript. Metabolomics services were performed by the Meta-bolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Biostatistics work is supported in part by the Biostatistics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313 to E.G. Hunt). Financial support from NCI/NIH is as follows: R01CA244361-01A1 and R01CA248359-01 (to J.E. Thaxton), T32 5T32AI132164-04 (to B.P. Riesenberg), T32 DE01755 (to M.D. Tennant), and T32 CA 193201 (to A.M. Andrews). The authors are
ASJC Scopus subject areas
- Oncology
- Cancer Research