Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy
Abstract Background Current checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microen...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2018-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-018-0401-3 |
| _version_ | 1818855336233140224 |
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| author | Guozhu Xie Tan Cheng Jie Lin Lanfang Zhang Jieling Zheng Ying Liu Guobo Xie Baiyao Wang Yawei Yuan |
| author_facet | Guozhu Xie Tan Cheng Jie Lin Lanfang Zhang Jieling Zheng Ying Liu Guobo Xie Baiyao Wang Yawei Yuan |
| author_sort | Guozhu Xie |
| collection | DOAJ |
| description | Abstract Background Current checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microenvironment is an important factor mediating the original resistance of tumors to immunotherapy. A previous report by our group has demonstrated that local angiotensin II (AngII) predominantly exists in a tumor hypoxic microenvironment where hypoxic tumour cells produced AngII by a hypoxia-lactate-chymase-dependent mechanism. Results Here, using 4T1 and CT26 syngeneic mouse tumor models, we found that local AngII in the tumor microenvironment was involved in immune escape of tumour cells and an AngII signaling blockage sensitized tumours to checkpoint immunotherapy. Furthermore, an AngII signaling blockage reversed the tumor immunosuppressive microenvironment, and inhibition of angiotensinogen (AGT, a precursor of AngII) expression strongly triggered an immune-activating cytokine profile in hypoxic mouse cancer cells. More importantly, AGT silencing combined with a checkpoint blockage generated an abscopal effect in resistant tumors. Conclusion Our study demonstrated an important role of local AngII in the formation of a tumor immunosuppressive microenvironment and its blockage may enhance tumor sensitivity to checkpoint immunotherapy. The combination of an AngII signaling blocker and an immune-checkpoint blockage could be a promising strategy to improve tumors responses to current checkpoint immunotherapy. |
| first_indexed | 2024-12-19T08:06:59Z |
| format | Article |
| id | doaj.art-93429b44b698470fbc419905c9b82b8a |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-19T08:06:59Z |
| publishDate | 2018-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-93429b44b698470fbc419905c9b82b8a2022-12-21T20:29:44ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262018-09-016111410.1186/s40425-018-0401-3Local angiotensin II contributes to tumor resistance to checkpoint immunotherapyGuozhu Xie0Tan Cheng1Jie Lin2Lanfang Zhang3Jieling Zheng4Ying Liu5Guobo Xie6Baiyao Wang7Yawei Yuan8Department of Radiation Oncology, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical UniversityDepartment of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical UniversityDepartment of Hepatopancreas Surgery, the First People’s Hospital of FoshanSchool of Computer Science and Technology, Guangdong University of TechnologyDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical UniversityAbstract Background Current checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microenvironment is an important factor mediating the original resistance of tumors to immunotherapy. A previous report by our group has demonstrated that local angiotensin II (AngII) predominantly exists in a tumor hypoxic microenvironment where hypoxic tumour cells produced AngII by a hypoxia-lactate-chymase-dependent mechanism. Results Here, using 4T1 and CT26 syngeneic mouse tumor models, we found that local AngII in the tumor microenvironment was involved in immune escape of tumour cells and an AngII signaling blockage sensitized tumours to checkpoint immunotherapy. Furthermore, an AngII signaling blockage reversed the tumor immunosuppressive microenvironment, and inhibition of angiotensinogen (AGT, a precursor of AngII) expression strongly triggered an immune-activating cytokine profile in hypoxic mouse cancer cells. More importantly, AGT silencing combined with a checkpoint blockage generated an abscopal effect in resistant tumors. Conclusion Our study demonstrated an important role of local AngII in the formation of a tumor immunosuppressive microenvironment and its blockage may enhance tumor sensitivity to checkpoint immunotherapy. The combination of an AngII signaling blocker and an immune-checkpoint blockage could be a promising strategy to improve tumors responses to current checkpoint immunotherapy.http://link.springer.com/article/10.1186/s40425-018-0401-3Renin-angiotensin systemAngiotensin IICheckpoint inhibitorImmunotherapyResistance |
| spellingShingle | Guozhu Xie Tan Cheng Jie Lin Lanfang Zhang Jieling Zheng Ying Liu Guobo Xie Baiyao Wang Yawei Yuan Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy Journal for ImmunoTherapy of Cancer Renin-angiotensin system Angiotensin II Checkpoint inhibitor Immunotherapy Resistance |
| title | Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy |
| title_full | Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy |
| title_fullStr | Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy |
| title_full_unstemmed | Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy |
| title_short | Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy |
| title_sort | local angiotensin ii contributes to tumor resistance to checkpoint immunotherapy |
| topic | Renin-angiotensin system Angiotensin II Checkpoint inhibitor Immunotherapy Resistance |
| url | http://link.springer.com/article/10.1186/s40425-018-0401-3 |
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