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.
Bibliographical noteFunding Information:
Study approval. All mice were maintained and handled in accordance with recommendations for the proper care and use of laboratory animals. The animal studies were conducted and performed under a protocol approved by the Korea University Institutional Animal Care and Use Committee (KUIACUC-2014-175). Approval for use of human material in research was obtained from the Korea Gynecologic Cancer Bank through the Bio and Medical Technology Development Program of the Ministry of Education, Science, and Technology (Seoul, South Korea).
We thank Emily Farmer for preparation of the manuscript and Lucy Wangaruro for administrative support (both from Johns Hopkins School of Medicine). This work was funded by the National Research Foundation of Korea (NRF-2017R1A2A1A17069818 and NRF-2013M3A9D3045881), the NIH Cervical Cancer Specialized Program of Research Excellence (SPORE) (P50 CA098252), the NIH Head and Neck Cancer SPORE (P50 CA96784-06), and NIH grant R01 CA114425-01.
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