CCAT1 Enhances NK Cells‐Mediated Antitumor Immunity in Hepatocellular Carcinoma

ABSTRACT Natural killer (NK) cells are innate lymphocytes, which are critical for the antitumor immunity response against tumour cells. However, the function of NK cells is frequently compromised in hepatocellular carcinoma (HCC). In this study, we found that CCAT1 expression level was reduced in peripheral blood (PB)‐NK cells derived from HCC patients, compared to PB‐NK cells derived from healthy controls. Reduced CCAT1 expression in NK cells was associated with poor disease‐free survival and overall survival of HCC patients. Gain‐ and loss‐of‐function assays revealed that CCAT1 restored NK cell cytotoxicity in vitro and also restored NK cell antitumor activity in vivo. Mechanistic investigations found that CCAT1 upregulated c‐Myc in NK cells. c‐Myc directly bound TBX21 promoter and activated TBX21 transcription, leading to the increase of T‐bet which is encoded by TBX21 . Through upregulating c‐Myc, CCAT1 increased T‐bet expression. Functional rescue assays showed that the function of CCAT1 in NK cells was dependent on c‐Myc and T‐bet. The expression of CCAT1 , MYC and TBX21 was positively correlated with each other in NK cells derived from HCC patients. Collectively, this study provided mechanistic insight into NK cell dysfunctionality in HCC and suggested that restoring CCAT1 in NK cells represented a potential NK‐cell‐targeting immunotherapeutic strategy for HCC.