AZD6738 Enhances The Anti-tumor Activity Of Radioimmunotherapy By Potentiating The Tumor Immune Microenvironment In Hepatocellular Carcinoma

BackgroundRadioimmunotherapy has a promising anti-tumor effect in hepatocellular carcinoma(HCC),depending on the regulatory effect of radiotherapy on tumor immune microenvironment.Ionizing radiation(IR)-induced DNA damage repair(DDR)pathway activation leads to the inhibition of immune microenvironment,thus impairing the anti-tumor effect of radioimmunotherapy.However,it is unclear whether inhibition of the DDR pathway can enhance the effect of radioimmunotherapy.In this study,we aim to explore the role of DDR inhibitor AZD6738 on the combination of radiotherapy and immune checkpoint inhibitors(ICIs)in HCCObjectivesTo explore the role of DDR inhibitor AZD6738 on the combination of radiotherapy and immune checkpoint inhibitors(ICIs)in HCC.Materials and methodsC5 7BL/6 mouse subcutaneous tumor model was used to evaluate the ability of different treatment regimens in tumor growth control and tumor recurrence inhibition.Effects of each treatment regimen on the alterations of immunophenotypes including the quantification,activation,proliferating ability,exhaustion marker expression,and memory status were assessed by flow cytometry.ResultsAZD6738 further increased radiotherapy-stimulated CD8+T cells infiltration and activation,and reverted the immunosuppressive effect of radiation on the number of Tregs in mice xenografts.Moreover,compared with radioimmunotherapy(radiotherapy plus anti-PD-L1),the addition of AZD6738 boosted the infiltration,increased cell proliferation,enhanced IFN-y production ability of TIL(tumor-infiltrating lymphocyte)CD8+T cells,and caused a decreasing trend in the number of TIL Tregs and exhausted T cells in mice xenografts.Thus,the tumor immune microenvironment was significantly improved.Meanwhile,triple therapy(AZD6738 plus radiotherapy plus anti-PD-L1)also induced a better immunophenotype than radioimmunotherapy in mice spleens.As a consequence,triple therapy displayed greater benefit in anti-tumor efficacy and mice survival than radioimmunotherapy.Mechanism study revealed that the synergetic antitumor effect of AZD6738 with radioimmunotherapy relied on the activation of cyclic GMP-AMP synthase/stimulator of interferon genes(cGAS/STING)signaling pathway.Furthermore,triple therapy led to stronger immunologic memory and lasting anti-tumor immunity than radioimmunotherapy,thus preventing tumor recurrence in mouse models.ConclusionsThis Our findings indicate that AZD6738 may be an optimal adjuvant treatment for radioimmunotherapy to control the proliferation of HCC cells,prolong survival and prevent tumor recurrence in HCC patients by improving immune microenvironment.