Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC

作者：Kun Li, Yihang Gong, Dongbo Qiu, Hui Tang, Jian Zhang, Zenan Yuan, Yingqi Huang, Yunfei Qin, Linsen Ye, Yang Yang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2021-004006 · 被引用次数：53 · 研究领域：interferon and immune responses、Cancer Immunotherapy and Biomarkers、Cancer, Hypoxia, and Metabolism

BACKGROUND: Emerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide, effectively promotes the therapeutic efficacy of programmed cell death protein-1 antibody (PD-1 Ab) through robust cGAS-STING activation. Unfortunately, the cGAS expression of tumor cells is reported to be severely suppressed by the hypoxic status in solid tumor. Clinically, enhancing chemotherapy-induced, DNA-activated tumor STING signaling by alleviating tumor hypoxia might be one possible direction for improving the currently poor response rates of patients with hepatocellular carcinoma (HCC) to PD-1 Ab. METHODS: Teniposide was first screened out from several chemotherapy drugs according to their potency in inducing cGAS-STING signaling in human HCC cells. Teniposide-treated HCC cells were then cultured under hypoxia, normoxia or reoxygenation condition to detect change in cGAS-STING signaling. Next, oxaliplatin/teniposide chemotherapy alone or combined with hyperbaric oxygen (HBO) therapy was administered on liver orthotopic mouse tumor models, after which the tumor microenvironment (TME) was surveyed. Lastly, teniposide alone or combined with HBO was performed on multiple mouse tumor models and the subsequent anti-PD-1 therapeutic responses were observed. RESULTS: Compared with the first-line oxaliplatin chemotherapy...