Antitumor T‐cell function requires CPEB4‐mediated adaptation to chronic endoplasmic reticulum stress

Abstract

Tumor growth is influenced by a complex network of interactions between multiple cell types in the tumor microenvironment (TME). These constrained conditions trigger the endoplasmic reticulum (ER) stress response, which extensively reprograms mRNA translation. When uncontrolled over time, chronic ER stress impairs the antitumor effector function of CD8 T lymphocytes. How cells promote adaptation to chronic stress in the TME without the detrimental effects of the terminal unfolded protein response (UPR) is unknown. Here, we find that, in effector CD8 T lymphocytes, RNA‐binding protein CPEB4 constitutes a new branch of the UPR that allows cells to adapt to sustained ER stress, yet remains decoupled from the terminal UPR. ER stress, induced during CD8 T‐cell activation and effector function, triggers CPEB4 expression. CPEB4 then mediates chronic stress adaptation to maintain cellular fitness, allowing effector molecule production and cytotoxic activity. Accordingly, this branch of the UPR is required for the antitumor effector function of T lymphocytes, and its disruption in these cells exacerbates tumor growth.

Terminal Unfolded Protein Responses-related genes predict prognosis and associate with proliferation and apoptosis in clear cell renal cell carcinoma

“…We compared immune cell in ltration in patients of two clusters and found an increased in ltration of most immune cells in cluster A patients, suggesting that immune in ltration in tumor tissue of patients was more abundant with higher TUPR-related gene signature and better response potential in immunotherapy of cluster A patients. It is worth noting that the in ltration of CD8 + T cells, which play a tumor-killing role, was signi cantly lower in cluster A than in cluster B patients, and we con rmed a higher T-cell dysfunction score in the cluster B, which may be related to ER stress-dependent T cell differentiation and development [43,44] . However, due to data limitations, our study of ccRCC patients was limited to the bulk RNA-seq analysis of the whole tumor tissue, and further analysis is needed to study the ER stress in speci c non-malignant cells in the TME of patients to explore the effect of TUPR on the function and characteristic remodeling of immune in ltrating cells.…”

circKDM1A suppresses bladder cancer progression by sponging miR-889-3p/CPEB3 and stabilizing p53 mRNA

“… 31 These proteins are widely expressed in tissues and tumors in partially overlapping patterns. 32 Our study is the first to report and elucidate the function and mechanism of CPEB3 in BCa. The protein has significantly low expression in BCa and is associated with a poor prognosis in patients with the disease.…”

Terminal Unfolded Protein Responses-related genes predict prognosis and associate with proliferation and apoptosis in clear cell renal cell carcinoma

“…It is worth noting that the in ltration of CD8+ T cells, which play a tumor-killing role, was signi cantly lower in cluster A than in cluster B patients, and we con rmed a higher T-cell dysfunction score in the cluster B, which may be related to ER stress-dependent T cell differentiation and development. 43,44 However, due to data limitations, our study of ccRCC patients was limited to the bulk RNA-seq analysis of the whole tumor tissue, and further analysis is needed to study the ER stress in speci c non-malignant cells in the TME of patients to explore the effect of TUPR on the function and characteristic remodeling of immune in ltrating cells.…”