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Abstract
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-1α 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.

Author information

Song KH1,2,3, Kim JH4, Lee YH1,2,3, Bae HC5, Lee HJ1,2,3, Woo SR1,2,3, Oh SJ1,2,3, Lee KM1,2, Yee C6, Kim BW7, Cho H4, Chung EJ8, Chung JY9, Hewitt SM9, Chung TW10, Ha KT10, Bae YK11, Mao CP12,13,14, Yang A14, Wu TC14,15,16,17, Kim TW1,2,3.
1
Department of Biochemistry and Molecular Biology.
2
Department of Biomedical Science, College of Medicine, and.
3
Translational Research Institute for Incurable Diseases, Korea University College of Medicine, Seoul, South Korea.
4
Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
5
Department of Orthopedic Surgery, Seoul National University Hospital, Seoul, South Korea.
6
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Department of Obstetrics and Gynecology, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Seoul, South Korea.
8
Radiation Oncology Branch and.
9
Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
10
Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, South Korea.
11
Comparative Biomedicine Research Branch, Research Institute, National Cancer Center, Goyang, South Korea.
12
MD-PhD Program.
13
Immunology Training Program.
14
Department of Pathology.
15
Department of Oncology.
16
Department of Obstetrics and Gynecology, and.
17
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.