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

Abstract

<div>Abstract<p>Cytotoxic CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy.</p><p><i><a href="https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-20-0649" target="_blank">See related article by Li et al., p. 154.</a></i></p></div>