journal contribution
posted on 2024-01-31, 15:20 authored by 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 Supplementary Figure from NKG7 Is a T-cell–Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy
Funding
High-Definition Therapeutics program
Mayo Clinic Center for Biomedical Discovery
Mayo Clinic Cancer Center's David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy program
Richard M. Schulze Family Foundation
Mayo Clinic Center for Clinical and Translational Science
NIH
National Institute of General Medical Sciences
History
ARTICLE 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.
