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

Abstract

BackgroundEmerging 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.MethodsTeniposide 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.ResultsCompared with the first-line oxaliplatin chemotherapy, teniposide chemotherapy induced stronger cGAS-STING signaling in human HCC cells. Teniposide-induced cGAS-STING activation was significantly inhibited by hypoxia inducible factor 1α in an oxygen-deficient environment in vitro and the inhibition was rapidly removed via effective reoxygenation. HBO remarkably enhanced the cGAS-STING-dependent tumor type Ⅰ interferon and nuclear factor kappa-B signaling induced by teniposide in vivo, both of which contributed to the activation of dendritic cells and subsequent cytotoxic T cells. Combined HBO with teniposide chemotherapy improved the therapeutic effect of PD-1 Ab in multiple tumor models.ConclusionsBy combination of two therapies approved by the Food and Drug Administration, we safely stimulated an immunogenic, T cell-inflamed HCC TME, leading to further sensitization of tumors to anti-PD-1 immunotherapy. These findings might enrich therapeutic strategies for advanced HCC andwe can attempt to improve the response rates of patients with HCC to PD-1 Ab by enhancing DNA-activated STING signaling through effective tumor reoxygenation.

Hypoxia signaling in cancer: Implications for therapeutic interventions

“…Studies have shown that atmospheric and hyperbaric hyperoxia can reduce the hypoxic area of tumors to varying degrees. [300][301][302][303] The EPO levels in hepatoblastoma HepG2 cells treated with 5% O 2 and 1% O 2 were 2.5 and 4 times higher than those in cells treated with 20% O 2 , respectively. In contrast, hyperoxia (40% O 2 ) significantly inhibited EPO production.…”

“…391,392 In a mouse model of bladder cancer treated with a combination of HBO and nimustine, there was a therapeutic effect on a subset of bladder tumors. 393 GBM is a highly malignant primary brain tumor originating from the glial tissue of the central nervous system, 394 and resistance to the chemotherapeutic drug temozolomide is commonly responsible for most 302 disease recurrences. [395][396][397] Experimental results showed that hyperoxia leads to dysregulation of protein folding, which in turn induces apoptosis mediated by the unfolded protein response.…”

Nanotechnological strategies to increase the oxygen content of the tumor

“…The development of efficient oxygen delivery strategies is valuable and significant for enhancing the effect of tumor therapy. At present, hyperbaric oxygen is inhaled and used clinically during tumor treatment to force more oxygen into the blood and tumors ( Chu et al, 2018 ; Liu et al, 2021 ; Li et al, 2022b ). However, this strategy cannot overcome the defect of insufficient oxygen supply caused by vessel structural abnormity, and it is difficult to effectively transport oxygen to the interior of the tumor.…”

The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway

“…Other reports showed that the hypoxic microenvironment within HCC inhibited the expression of cGAS. Therefore, cGAS-mediated DNA recognition and STING-TBK1-IRF3 pathway activation were inhibited [ 87 , 88 ]. Moreover, some tumors can evade the immune system by suppressing STING.…”