ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma

Abstract

BackgroundRadioimmunotherapy has a promising antitumor 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 antitumor 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 HCC.MethodsC57BL/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 cell 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 (Programmed death ligand 1)), the addition of AZD6738 boosted the infiltration, increased cell proliferation, enhanced interferon (IFN)-γ 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 antitumor efficacy and mice survival than radioimmunotherapy. Mechanism study revealed that the synergistic 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 antitumor immunity than radioimmunotherapy, thus preventing tumor recurrence in mouse models.ConclusionsOur findings indicate that AZD6738 might be a potential synergistic treatment for radioimmunotherapy to control the proliferation of HCC cells, prolong survival, and prevent tumor recurrence in patients with HCC by improving the immune microenvironment.

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

“…ATR inhibition potentiated type I IFN production in concert with IR in a cGAS–STING-dependent manner [ 97 ]. Moreover, ATR inhibition in combination with IR and immune checkpoint blockade resulted in superior antitumor efficacy in hepatocellular carcinoma models in a cGAS–STING-mediated manner [ 123 ]. As mentioned previously, one of the drawbacks of radiation-induced activation of the STING pathway is recruitment of immunosuppressive MDSCs to the TME [ 113 ].…”

Integrative Analysis of Genes Associated With Cancer Stem Cell Characteristics via Stemness Indices Combined With Multi-Omics Data in Liver Cancer

“…The immune microenvironment plays a positive and negative role in the occurrence, development and invasion of cancer. In general, the stronger the immune cell invasion in the tumor microenvironment, the more able to inhibit tumor progression [39][40][41][42]. There are three processes in the immune response of cancer: elimination, balance and escape.…”

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

“…Various studies have shown that other DDR inhibitors, such as ATR, WEE1, and CHK1 inhibitors, have synergistic effects with immune checkpoint inhibitors. Sheng et al [150] demonstrated that AZD6738 enhances the efficacy of immune checkpoint inhibitors and radiotherapy in hepatocellular carcinoma. The synergistic antitumor effect of AZD6738 and radioimmunotherapy combination therapy depended on cyclic GMP-AMP synthase (cGAS)/STING signaling pathway activation.…”