期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 9, 页码 4098-4114出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI96804
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资金
- National Research Foundation of Korea [NRF-2017R1A2A1A17069818, NRF-2013M3A9D3045881]
- NIH Cervical Cancer Specialized Program of Research Excellence (SPORE) [P50 CA098252]
- NIH Head and Neck Cancer SPORE [P50 CA96784-06]
- NIH [R01 CA114425-01]
- NATIONAL CANCER INSTITUTE [P50CA098252] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007309] Funding Source: NIH RePORTER
The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1 alpha stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.
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