CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma

Abstract

A major obstacle to effective cancer immunotherapy is the tumor immune microenvironment. Natural killer (NK) cell resistance has been suggested as a primary cause of poor prognosis in hepatocellular carcinoma (HCC), which seemingly correlates with CNOT7 overexpression. CNOT7, a cytoplasmic mRNA deadenylase that is highly expressed in HCC, may regulate cytokine transforming growth factor‐β1 (TGF‐β1) secretion by controlling nuclear factor‐κB subunit p65 trafficking. CNOT7 depletion suppresses TGF‐β1 secretion in HCC and promotes interferon‐γ (IFN‐γ) secretion by NK cells, and we previously demonstrated that CNOT7 depletion reversed IFN‐γ resistance in HCC cells. Therefore, we hypothesized that CNOT7 depletion might reverse NK cell resistance by influencing the tumor immune microenvironment of HCC. To test this hypothesis, we examined the correlation between CNOT7, STAT1, TGF‐β1 and IFN‐γ expression with hepatitis B virus‐related cirrhosis and HCC with hepatitis B virus‐related cirrhosis. We found that modulation of CNOT7 expression alters TGF‐β1 secretion in HCC and IFN‐γ secretion in NK cells. We also examined the effects of NK cells in HepG2 cells with CNOT7 knockdown, which showed that NK cell surface CD107a expression is up‐regulated and caspase‐3 expression is significantly enhanced in CNOT7‐deficient HepG2 cells. Overall, our results show that knockdown of CNOT7 expression reverses NK cell resistance in HCC cells. Therefore, CNOT7 depletion has potential as a new adjuvant therapy in immunotherapy for HCC.

CD168+ macrophages promote hepatocellular carcinoma tumor stemness and progression through TOP2A/β-catenin/YAP1 axis

“…ELISA was performed as as described above. 86 In this study, the supernatant of tumor cells after co-culture was used for the determination of CXCL12 and TGF-β1. The testing process was carried out in full accordance with the product instructions.…”

Overcoming the therapeutic resistance of hepatomas by targeting the tumor microenvironment

“…NK cell abnormalities induced by the TME are the main reason why tumor cells escape the immune response. Similarly, the inhibition of CNOT7 and the enhancement of zeste homolog 2 (EZH2), miR-889, granulin-epithelin precursor (GEP), and MICA/B can successfully reverse NK cell resistance, suggesting that these molecules are promising targets for immunotherapy in HCC patients (105)(106)(107)(108)(109).…”

Promoting expression of IP-10 and chemotaxis of γδT cells by silencing CNOT7 of HepG2 cells in vitro

“…So far, 11 CNOT subunits (CNOT1-11) have been identified [22]and among them, CNOT7 is the main devinylase of the eukaryotic clock, which plays an important role in maintaining cell viability [23,24]. In HCC, the high expression of CNOT7 will lead to the decrease of STAT1 expression and the worse prognosis of HCC patients [25]. Silencing CNOT7 could up-regulates the expression of STAT1 regulatory genes through enhancing the promoter occupancy of STAT1 [26].…”