Research On The Regulation Mechanism Of Anti-tumor Response Of NK Cells

Natural Killer Cell(NK),named for killing tumor cells or virally infected cells without prior sensitivity,is the first line of defense for human immune surveillance.Cell redox level plays a key role in human diseases and participates in the development of tumors to varying degrees.It is not clear how some characteristic molecules of tumor cells,especially redox levels,affect the immune response of NK cells to tumors.Therefore,the purpose of this study is to reveal the effect and mechanism of the redox level of tumor cells on NK cell anti-tumor response.Thioredoxin-Interacting Protein(TXNIP)is an important redox-regulating molecule in cells.It binds to thioredoxin and inhibits its antioxidative effect,leaving cells in an oxidative stress state.TXNIP has decreased expression to varying degrees in various cancer tissues and cell lines,and after improving the expression of TXNIP,the proliferation of cancer cells is affected and even induces cancer cells to apoptosis.As a result,TXNIP is considered an attractive target for the development of drugs for many human diseases.TXNIP is closely related to redox imbalance in tumor cells and decreased anti-tumor activity in NK cells,but there is little research on the effect of high oxidation levels of tumor cells on NK cell anti-tumor response.Therefore,it is of great significance to study the redox level of tumor cells and its mechanism of anti-tumor response in NK cells by using redox-regulating molecule TXNIP.Given that the TXNIP gene is expressed in normal tissues,and low expression in multiple tumor tissues,and the mouse T lymphoma cell line RMAS is a NK cell-sensitive target cell.Therefore,in this study we chose to overexpress TXNIP gene in RMAS cells,found that overexpression TXNIP did not affect RMAS cell proliferation and apoptosis,and improved the killing of RMAS cells by NK cells,indicating that overexpression of TXNIP in tumor cells increased the sensitivity of tumor cells to cytotoxicity of NK cells.TXNIP has the function of regulating redox,so we tested the level of reactive oxygen cluster(ROS)in RMAS cells thatoverexpressed TXNIP.As a result,the ROS level in the experimental group was significantly higher than that in the control group,indicating that raising the ROS of tumor cells can increase the sensitivity of tumor cells to cytotoxicity of NK cells.Cell killing is the main way of NK cell anti-tumor.Therefore,under the premise that overexpression of TXNIP improves the sensitivity of tumor cells to cytotoxicity of NK cells,we established tumor models in immune-competent mice and NK cell-clearing mice,and studied the effect of overexpressive TXNIP on NK cell antitumor function under physiological conditions.The results showed that tumor growth was slower than in the control group in the immune-competent mice model,and there was no difference in tumor growth rate in the NK cell-clearing mice model.These in vivo data show that TXNIP is overexpressed in tumor cells,inhibiting tumor growth in a manner dependent on the presence of NK cells.In summary,improving the level of TXNIP in tumor cells,can improve the sensitivity of tumor cells to cytotoxicity of NK cells and relying on the presence of NK cells to inhibit tumor development.This study suggests that TXNIP,a redox regulator in tumor cells,may become a potential target for regulating NK cell anti-tumor response.