NKG7 Is a T-cell-Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy.
Ti WenWhitney BarhamYing LiHenan ZhangJoanina K GicobiJacob B HirdlerXin LiuHyoungjun HamKodi E Peterson MartinezFabrice LucienRoxane R LavoieHu LiCristina CorreiaDileep D MonieZesheng AnSusan M HarringtonXiaosheng WuRuifeng GuoRoxana S DroncaAaron S MansfieldYiyi YanSvetomir N MarkovicSean S ParkJie SunHong QinMinetta C LiuGeorge VasmatzisDaniel D BilladeauHaidong DongPublished in: Cancer immunology research (2021)
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.
Keyphrases
- nk cells
- cell therapy
- single cell
- natural killer cells
- endothelial cells
- poor prognosis
- transcription factor
- highly efficient
- rna seq
- binding protein
- stem cells
- mesenchymal stem cells
- induced pluripotent stem cells
- high throughput
- induced apoptosis
- pluripotent stem cells
- combination therapy
- signaling pathway
- bone marrow
- dna binding
- protein protein