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

Ti Wen, Whitney Barham, Ying Li, Henan Zhang, Joanina K. Gicobi, Jacob B. Hirdler, Xin Liu, Hyoungjun Ham, Kodi E. Peterson Martinez, Fabrice Lucien, Roxane R. Lavoie, Hu Li, Cristina Correia, Dileep D. Monie, Zesheng An, Susan M. Harrington, Xiaosheng Wu, Ruifeng Guo, Roxana S. Dronca, Aaron S. MansfieldYiyi Yan, Svetomir N. Markovic, Sean S. Park, Jie Sun, Hong Qin, Minetta C. Liu, George Vasmatzis, Daniel D. Billadeau, Haidong Dong

Research output: Contribution to journalArticlepeer-review

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 (NKG7). 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 NKG7 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 in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen-specific CD8 T cells in an in vivo 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.

Original languageEnglish (US)
Pages (from-to)162-181
Number of pages20
JournalCancer Immunology Research
Volume10
Issue number2
DOIs
StatePublished - Feb 2022

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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