Ablation of T cell–associated PD-1H enhances functionality and promotes adoptive immunotherapy

Abstract

Programmed death-1 homolog (PD-1H) is a co-inhibitory molecule that negatively regulates T cell-mediated immune responses. In this study, we determined whether ablation of T cell-associated PD-1H could enhance adoptive T cell therapy in experimental tumor models. The expression of PD-1H is up-regulated in activated and tumor-infiltrating CD8 + T cells. Activated CD8 + T cells from PD-1H deficient (KO) mice exhibited increased cell proliferation, cytokine production and anti-tumor activity in vitro. Adoptive transfer of PD-1H-KO CD8 + T cells resulted in the regression of established syngeneic mouse tumors. Similar results were obtained when PD-1H was ablated in T cells by CRISPR/Cas9-mediated gene silencing. Furthermore, ablation of PD-1H in CAR-T cells significantly improved their anti-tumor activity against human xenografts in vivo. Our results indicate that T cell-associated PD-1H could suppress immunity in the tumor microenvironment and targeting PD-1H may improve T cell adoptive immunotherapy.

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

“…By directly removing or blocking the immune checkpoints on CAR-T cells, their inhibitory effects might be avoided and therefore the anti-tumor effects of CAR-T cells are promoted. For example, the production of PD-1 resistant CD19-, CD133and C-type lectin-like molecule-1 (CLL-1)-CAR-T cells achieved by the knockout of PD-1/PD-1 homolog genes can enhance CAR-T cell therapy (42)(43)(44). Recently, two relapsed/refractory AML patients who received HSCT and CD38-CAR-T cell therapy before showed continuous remission after receiving PD-1-silenced CLL-1-CAR-T cell therapy (45).…”