| First Author | Riesenberg BP | Year | 2022 |
| Journal | Cancer Res | Volume | 82 |
| Issue | 23 | Pages | 4386-4399 |
| PubMed ID | 36126165 | Mgi Jnum | J:331950 |
| Mgi Id | MGI:7397309 | Doi | 10.1158/0008-5472.CAN-22-1744 |
| Citation | Riesenberg BP, et al. (2022) Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer. Cancer Res 82(23):4386-4399 |
| abstractText | 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 eIF2alpha (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2alpha undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2alpha accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2alpha 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. SIGNIFICANCE: Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfolded protein response induced by stress in the tumor microenvironment. |
