Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC
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 effic...
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BMJ Publishing Group
2022-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/8/e004006.full |
| _version_ | 1811283474082955264 |
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| author | Jian Zhang Hui Tang Yang Yang Kun Li Linsen Ye Yihang Gong Dongbo Qiu Zenan Yuan Yingqi Huang Yunfei Qin |
| author_facet | Jian Zhang Hui Tang Yang Yang Kun Li Linsen Ye Yihang Gong Dongbo Qiu Zenan Yuan Yingqi Huang Yunfei Qin |
| author_sort | Jian Zhang |
| collection | DOAJ |
| description | 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, 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.Conclusions By 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. |
| first_indexed | 2024-04-13T02:13:15Z |
| format | Article |
| id | doaj.art-fa2220b57c634c489227ee7b0f129e64 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-13T02:13:15Z |
| publishDate | 2022-08-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-fa2220b57c634c489227ee7b0f129e642022-12-22T03:07:15ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-08-0110810.1136/jitc-2021-004006Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCCJian Zhang0Hui Tang1Yang Yang2Kun Li3Linsen Ye4Yihang Gong5Dongbo Qiu6Zenan Yuan7Yingqi Huang8Yunfei Qin9Department of Neurosurgery, Shanghai Jiaotong University School of Medicine, Xinhua Hospital Chongming Branch, Shanghai, ChinaDivision of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USADepartment of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China1 Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, ChinaAff1 0000 0004 1762 1794grid.412558.fDepartment of Hepatic Surgery and Liver Transplantation CenterThe Third Affiliated Hospital of Sun Yat-sen University Guangzhou ChinaDepartment of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaVaccine Research Institute, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaDepartment of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaDepartment of Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaDepartment of Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaBackground 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, 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.Conclusions By 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.https://jitc.bmj.com/content/10/8/e004006.full |
| spellingShingle | Jian Zhang Hui Tang Yang Yang Kun Li Linsen Ye Yihang Gong Dongbo Qiu Zenan Yuan Yingqi Huang Yunfei Qin Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC Journal for ImmunoTherapy of Cancer |
| title | Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC |
| title_full | Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC |
| title_fullStr | Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC |
| title_full_unstemmed | Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC |
| title_short | Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC |
| title_sort | hyperbaric oxygen facilitates teniposide induced cgas sting activation to enhance the antitumor efficacy of pd 1 antibody in hcc |
| url | https://jitc.bmj.com/content/10/8/e004006.full |
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