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

Abstract

Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of Tcells 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 Tcell receptor (TCR) signaling in T and natural killer (NK) cells. However, its role in the regulation of immune checkpoints in Tcells remains unclear. In this study, we ablated CISH in Tcells with CRISPR-Cas9 and found that the sensitivity of Tcells to TCR and cytokine stimulation was increased. In addition, chimeric antigen receptor Tcells with CISH deficiency exhibited longer survival and higher cytokine secretion and antitumor activity. Notably, PD-1 expression was decreased in activated CISH-deficient Tcells invitro and invivo. The level of FBXO38, a ubiquitination-regulating protein that reduces PD-1 expression, was elevated in activated Tcells 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.