1. RAC1high NK cell-based immunotherapy in hepatocellular carcinoma via STAT3-NKG2D axis.
- Author
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Shi, Xiaoli, Chen, Wenwei, Yin, Yefeng, Cao, Hengsong, Wang, Xinyi, Jiang, Wangjie, Li, Qing, Li, Xiangcheng, Yu, Yue, and Wang, Xuehao
- Subjects
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KILLER cells , *CELL-mediated cytotoxicity , *MACHINE learning , *IMMUNOTHERAPY , *PROMOTERS (Genetics) , *HEPATOCELLULAR carcinoma - Abstract
Natural killer (NK) cells exert an indispensable role in innate immune responses against cancer progression, however NK cell dysfunction has been rarely reported in hepatocellular carcinoma (HCC). This study sought to uncover the immunoregulatory mechanisms of tumor-infiltrating NK cells in HCC. A consensus NK cell-based signature (NKS) was constructed using integrative machine learning algorithms based on multi-omics data of HCC patients. HCC tumors had lower numbers of infiltrating NK cells than para-tumor normal liver tissues. Based on the NK cell-associated genes, the NKS was built for HCC prognostic prediction and clinical utilities. Drug targets and novel compounds were then identified for high-NKS groups. RAC1 was confirmed as the hub gene in the NKS genes. RAC1 was upregulated in HCC tumors and positively correlated with shorter survival time. RAC1 overexpression in NK-92 cells facilitated the cancer-killing capacity by the anticancer cytotoxic effectors and the upregulated NKG2D. The survival time of PDX-bearing mice was also prolonged upon NK-92RAC1 cells. Mechanistically, RAC1 interacted with STAT3 and facilitated its activation, thereby enabling its binding to the promoter region of NKG2D and functioning as a transcriptional regulator in NK-92 via molecular docking, Co-IP assay, CHIP and luciferase experiments. Collectively, our study describes a novel function of RAC1 in potentiating NK cell-mediated cytotoxicity against HCC, highlighting the clinical utilities of NKS score and RAC1high NK cell subset in HCC immunotherapy. • A novel NK cell-based signature (NKS) for HCC prognosis prediction and potential therapeutic targets was established by machine learning algorithms based on multi-omics data. • RAC1high NK cell subset enhanced the cancer-killing capacity by activating STAT3 and upregulating NKG2D against HCC cells. • RAC1high NK cells effectively inhibited the aggressiveness of HCC cells in vitro and in vivo, especially in patient-derived xenograft (PDX) models. • RAC1high NK cells might be a promising therapeutic option for HCC patients, especially for those with high NKS scores. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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