Disruption of CISH promotes the antitumor activity of human T cells and decreases PD-1 expression levels

• Published in: Molecular therapy. Oncolytics 2023-03, Vol.28, p.46-58
• Main Authors: Lv, Jiang, Qin, Le, Zhao, Ruocong, Wu, Di, Wu, Zhiping, Zheng, Diwei, Li, Siyu, Luo, Mintao, Wu, Qiting, Long, Youguo, Tang, Zhaoyang, Tang, Yan-Lai, Luo, Xuequn, Yao, Yao, Yang, Li-Hua, Li, Peng
• Format: Article
• Language: English
• Subjects: chimeric antigen receptor T cells; CISH; CRISPR-Cas9; FBXO38; immunotherapy; Original; PD-1
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2022.12.003

Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of T cells through immune checkpoints, including the PD-L1/PD-1 axis. Cytokine-inducible SH2-containing protein (CISH), a member of the suppressor of cytokine signaling (SOCS) family, inhibits JAK-STAT and T cell receptor (TCR) signaling in T and natural killer (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. [Display omitted] Li and colleagues discovered a way to reduce PD-1 expression in activated T cells and promote T cell function by knocking out the suppressor gene CISH. This is an effective and feasible way to modulate T cell immune function, especially for enhancing the effect of clinical CAR-T cell therapy.