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 (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.See related article by Li et al., p. 154.

• Authors: 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 Mansfield, Yiyi Yan, Svetomir N Markovic, Sean S Park, Jie Sun, Hong Qin, Minetta C Liu, George Vasmatzis, Daniel D Billadeau, Haidong Dong
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 10 Issue 2 Pg. 162-181 (02 2022) ISSN: 2326-6074 [Electronic] United States
• PMID: 34911739 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Membrane Proteins
• NKG7 protein, human
• Nkg7 protein, mouse
• RNA, Messenger

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Humans
• Immunotherapy
• Membrane Proteins (metabolism)
• Mice
• Neoplasms (immunology, therapy)
• RNA, Messenger (therapeutic use)
• T-Lymphocytes, Cytotoxic