The Wnt Pathway Inhibitor PRI-724 Enhances Antitumor Effect Of Radiation Therapy In Liver Cancer By Improving Immune Microenvironment

BackgroundHepatocellular carcinoma(HCC)is one of the most common lethal tumors.Among the most common tumors in China,the incidence of hepatocellular carcinoma is the fourth,and the mortality rate is the second.The 5-year survival rate of liver cancer is only 14.1%.Most patients with liver cancer are diagnosed as advanced,and most patients with advanced liver cancer and recurrent liver cancer still lack safe and effective treatment.Radiotherapy can increase the efficacy of immunotherapy by changing the tumor immune microenvironment.The Wnt pathway is an important messenger in the tumor microenvironment,which affects the expression of various immune factors and is closely related to the regulation of the immune microenvironment,and the dysregulation of Wnt signaling is related to the radioresistance of various cancers.Therefore,inhibitors of the Wnt pathway may improve the tumor immune microenvironment after radiotherapy and cooperate with radiosensitization to enhance the antitumor effect of radiotherapy in hepatocellular carcinoma.ObjectivesThis article mainly evaluates the anti-tumor effect of Wnt signal inhibitor combined with radiotherapy on liver cancer,and explores its effect on the immune microenvironment after radiotherapy in the treatment of hepatocellular carcinoma.Materials and methodsFirstly,we used C57BL/6 mice and BALB/c nude mice subcutaneous tumor models to evaluate radiation therapy,PRI-724(small molecule Wnt signaling inhibitor)therapy,radiation therapy combined with Wnt pathway inhibitor.The ability of treatment to control tumor growth and inhibit tumor recurrence.Then the subcutaneous tumors were extracted,and the tumor immune microenvironment in the subcutaneous tumors of each group of mice was analyzed by flow cytometry.The effects of Wnt pathway inhibitors on the immune phenotype were explored.Finally,Western blot detection was used to detect silenced β-catenin expression of immune factors in liver cancer cells.ResultsWnt pathway inhibitor combined with radiation therapy show significant benefits in terms of anti-tumor efficacy and mouse survival in vivo,as well as inhibition of tumor recurrence,compared with radiation therapy alone.The anti-tumor effect of combination therapy is more obvious in immune-bearing tumor-bearing mice.Wnt pathway inhibitors can increase the infiltration of lymphocytes CD8+T lymphocytes,M1 type macrophages,etc.in the tumor,and improve the tumor immune microenvironment after radiotherapy.Inhibition of the Wnt pathway can induce increased expression of IFN-y by immune cells in the tumor microenvironment,and at the same time increase the expression of interferon y receptor 1 in liver cancer cells.By enhancing the interferon pathway to kill tumor cells,a better anti-tumor effect is obtained.ConclusionsIn the treatment of hepatocellular carcinoma,the suppression of the Wnt pathway based on radiation therapy can increase the expression of interferon gamma receptor 1 in hepatoma cells.At the same time,it can increase the number of CD8+T lymphocytes in the tumor microenvironment after radiotherapy and induce its expression of IFN-γ,enhance the killer function of effector cells,and then increase the infiltration of macrophages in the microenvironment,thereby improving the immune microenvironment after radiotherapy.In addition,the inactivation of the Wnt pathway affects the cell damage and repair of tumor cells after radiotherapy,reduces the radioresistance of liver cancer cells,and thereby synergistically exerts a killing effect on tumors,prolongs the survival period of tumor-bearing mice and improves their tumor control rate.Our findings suggest that the Wnt pathway inhibitor may be an effective adjuvant for radiotherapy in patients with hepatocellular carcinoma,providing a basis for future clinical research on hepatocellular carcinoma.