TY - JOUR
T1 - NKG7 Is a T-cell-Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy
AU - Wen, Ti
AU - Barham, Whitney
AU - Li, Ying
AU - Zhang, Henan
AU - Gicobi, Joanina K.
AU - Hirdler, Jacob B.
AU - Liu, Xin
AU - Ham, Hyoungjun
AU - Peterson Martinez, Kodi E.
AU - Lucien, Fabrice
AU - Lavoie, Roxane R.
AU - Li, Hu
AU - Correia, Cristina
AU - Monie, Dileep D.
AU - An, Zesheng
AU - Harrington, Susan M.
AU - Wu, Xiaosheng
AU - Guo, Ruifeng
AU - Dronca, Roxana S.
AU - Mansfield, Aaron S.
AU - Yan, Yiyi
AU - Markovic, Svetomir N.
AU - Park, Sean S.
AU - Sun, Jie
AU - Qin, Hong
AU - Liu, Minetta C.
AU - Vasmatzis, George
AU - Billadeau, Daniel D.
AU - Dong, Haidong
N1 - Funding Information:
We thank all the patients who generously contributed samples and participated in the study. We also acknowledge the Division of Medical Oncology at the Mayo Clinic for providing excellent patient care. This study was supported in part by the generosity of Mayo Clinic benefactors. We acknowledge the Genome Analysis Core at Mayo Clinic, Rochester, including technologists Vernadette A. Simon and Fariborz Rakh-shan-Rohakhtar as well as supervisors Julie S. Lau, Samantha J. McDonough, and Mark Mutawe. We are grateful for the electron microscopy imaging service provided by Bing Huang and Scott I. Gamb at the Mayo Clinic Microscope and Cell Analysis Core. BioRender.com was used to create the graphics throughout the manuscript.
Funding Information:
We acknowledge support from the Mayo Clinic Center for Individualized Medicine’s IMPRESS program and High-Definition Therapeutics program (to H. Dong), the Mayo Clinic Center for Biomedical Discovery (to H. Dong), the Mayo Clinic Cancer Center’s David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy program (H. Dong, D.D. Billadeau), the Richard M. Schulze Family Foundation (to H. Dong), the Innovation Accelerator Awards program of the Office of Translation to Practice (OTP) at the Mayo Clinic Center for Clinical and Translational Science (CCaTS), NIH grant F30 CA250326 (to W. Barham), NIH grant F30 CA250122 (to D.D. Monie), National Institute of General Medical Sciences T32 GM65841 (to W. Barham and D.D. Monie), NIH grant R21 CA251923 (to A.S. Mansfield), NIH grant K12 CA 090628 (to Y. Yan), NIH grant R21 CA197878 (to H. Dong), NIH grant R01 AI095239 (to H. Dong), NIH grant R01 CA200551 (to H. Dong and S.S Park), and NIH grant R01 CA256927 (to H. Dong).
Funding Information:
D.D. Monie reports grants from NCI during the conduct of the study. A.S. Mansfield reports other support from Genentech, AbbVie, Bristol Myers Squibb, Janssen, and Shanghai Roche Pharmaceuticals and grants from Mark Foundation, NIH, and DoD outside the submitted work, and is a nonremunerated director of the Mesothelioma Applied Research Foundation. S.N. Markovic reports grants from NIH during the conduct of the study, as well as grants from Bristol Myers Squibb and Sorrento Therapeutics outside the submitted work. S.S. Park reports grants from MacroGenics and NCI, and other support from AstraZeneca outside the submitted work. M.C. Liu reports other support from Eisai, Genentech, Merck, Novartis, Seattle
Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-21-0539
DO - 10.1158/2326-6066.CIR-21-0539
M3 - Article
C2 - 34911739
AN - SCOPUS:85124056928
VL - 10
SP - 162
EP - 181
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 2
ER -