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

Autor:	Wen T; Department of Urology, Mayo Clinic, Rochester, Minnesota., Barham W; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Li Y; Division of Computational Biology, Mayo Clinic, Rochester, Minnesota., Zhang H; Department of Urology, Mayo Clinic, Rochester, Minnesota., Gicobi JK; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Hirdler JB; Department of Urology, Mayo Clinic, Rochester, Minnesota., Liu X; Department of Urology, Mayo Clinic, Rochester, Minnesota., Ham H; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Peterson Martinez KE; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Lucien F; Department of Urology, Mayo Clinic, Rochester, Minnesota., Lavoie RR; Department of Urology, Mayo Clinic, Rochester, Minnesota., Li H; Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Correia C; Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Monie DD; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., An Z; Department of Urology, Mayo Clinic, Rochester, Minnesota., Harrington SM; Department of Urology, Mayo Clinic, Rochester, Minnesota., Wu X; Division of Hematology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Guo R; Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota., Dronca RS; Division of Medical Oncology, Mayo Clinic, Jacksonville, Florida., Mansfield AS; Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota., Yan Y; Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota., Markovic SN; Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota., Park SS; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota., Sun J; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota., Qin H; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida., Liu MC; Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota., Vasmatzis G; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota., Billadeau DD; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota., Dong H; Department of Urology, Mayo Clinic, Rochester, Minnesota. dong.haidong@mayo.edu.; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2022 Feb; Vol. 10 (2), pp. 162-181. Date of Electronic Publication: 2021 Dec 15.
DOI:	10.1158/2326-6066.CIR-21-0539
Abstrakt:	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. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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