NKG7 Is a T-cell–Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy

Abstract

Cytotoxic CD8⁺ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8⁺ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8⁺ T cells from patients treated with anti-PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (<i>NKG7</i>). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8⁺ T-cell-mediated killing of tumor cells. Transfection of T cells with <i>NKG7</i> mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti-PD-1 or anti-PD-L1 therapy <i>in vitro</i>. <i>NKG7</i> mRNA therapy also improved the antitumor activity of murine tumor antigen-specific CD8⁺ T cells in an <i>in vivo</i> model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8⁺ T cells and establish NKG7 as a T-cell-intrinsic therapeutic target for enhancing cancer immunotherapy.<i>See related article by Li et al., p. 154.</i>