Abstract
Programmed death-1 homolog (PD-1H) is a coinhibitory 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 upregulated in activated and tumor-infiltrating CD8+ T cells. Activated CD8+ T cells from PD-1H–deficient (PD-1H–KO) mice exhibited increased cell proliferation, cytokine production, and antitumor 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 antitumor activity against human xenografts in vivo. Our results indicate that T cell–associated PD-1H could suppress immunity in the tumor microenvironment and that targeting PD-1H may improve T cell adoptive immunotherapy.
Highlights
Programmed death-1 homolog (PD-1H, called VISTA, VSIR, Dies1, Gi24, DD1α) is a member of the B7-CD28 family of cell membrane proteins [1, 2]
These results suggest that PD-1H may be induced in antigen-activated T cells
CD8+ T cells express lower levels of PD-1H in their inactivated status compared to CD4+ T cells, which may be attributed to PD-1H more prone to be upregulated in CD8+ T cells
Summary
Programmed death-1 homolog (PD-1H, called VISTA, VSIR, Dies, Gi24, DD1α) is a member of the B7-CD28 family of cell membrane proteins [1, 2]. Despite an overall hyperresponsive to antigen stimulation, there was no obvious autoimmune phenotypes developed in PD-1H KO mice [5, 7], implicating that PD-1H is a molecule involved in fine-tuning of immune responses but not a major protein in the suppression of autoimmunity. Consistent to these findings, a recent study reveals that PD-1H regulates quiescence of CD4+ T cells [9]. Treatment with PD-1H agonistic mAbs reduced severity of autoimmune diseases in the mouse models of lupus [13], asthma [14, 15] and arthritis [16]
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