2026-10-12T10:33:50Z https://www.scidb.cn/oai

10.57760/sciencedb.06953 2022-12-22T10:29:31Z

2022-12-22 Disruption of CISH promotes the antitumor activity of human T cells and decreases PD-1 expression levels doi:10.57760/sciencedb.06953 en Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of T cells through immune checkpoints, including the PD-L1/PD-1 axis. CISH, a member of the SOCS family, inhibits JAK-STAT and TCR signaling in T and NK cells. However, its role in the regulation of immune checkpoints in T cells remains unclear. In this study, we ablated CISH in T cells with CRISPR/Cas9 and found that the sensitivity of T cells to TCR and cytokine stimulation was increased. In addition, chimeric antigen receptor T cells with CISH deficiency exhibited longer survival and higher cytokine secretion and antitumor activity. Notably, PD-1 expression was decreased in activated CISH-deficient T cells in vitro and in vivo. The level of FBXO38, a ubiquitination-regulating protein that reduces PD-1 expression, was elevated in activated T cells after CISH ablation. Hence, this study reveals a mechanism by which CISH promotes PD-1 expression by suppressing the expression of FBXO38 and proposes a new strategy for augmenting the therapeutic effect of CAR-T cells by inhibiting CISH. Chimeric antigen receptor T cells; Immunotherapy; CISH; PD-1; FBXO38; CRISPR/Cas9 Jiang Lv Le Qin Ruocong Zhao Di Wu Zhiping Wu Diwei Zheng Siyu Li Mintao Luo Qiting Wu Youguo Long Zhaoyang Tang Yan-Lai Tang Xuequn Luo Yao Yao Li-Hua Yang Peng Li PUBLIC https://creativecommons.org/licenses/by/4.0/ dataset Science Data Bank