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

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.

CAR designs for solid tumors: overcoming hurdles and paving the way for effective immunotherapy.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized immunotherapy by modifying patients' immune cells genetically. By expressing CARs, these modified cells can specifically identify and eliminate tumor cells. The success of CAR-T therapy in hematological malignancies, such as leukemia and lymphoma, has been remarkable. Numerous studies have reported improved patient outcomes and increased survival rates. However, the application of CAR-T therapy in treating solid tumors faces significant challenges. Solid tumors possess complex microenvironments containing stromal cells, extracellular matrix components, and blood vessels. These factors can impede the infiltration and persistence of CAR-T cells within the tumor. Additionally, the lack of target antigens exclusively expressed on tumor cells raises concerns about off-target effects and potential toxicity. This review aims to discuss advancements achieved by CAR-T therapy in solid tumors and the clinical outcomes in the realm of solid tumors.