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Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia
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Abstract
Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9–16. ©2016 AACR.
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“Current studies have focused on the role of hypoxia-induced metabolic reprogramming in causing T cell dysfunction and exhaustion16,19,52–55.”
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Citations
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Background
Cited by
Sorted by citations
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 2,054
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Vitale, I., Manic, G., Coussens, L. M., Kroemer, G., & Galluzzi, L. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.001 · Cited by 1,837
Metabolic Instruction of Immunity
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The updated landscape of tumor microenvironment and drug repurposing
Jin, M.-Z., & Jin, W.-L. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00280-x · Cited by 1,262
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Gao, W., Wang, Y., Zhou, Y., Wang, X., & Yu, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01046-3 · Cited by 1,097
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Background
Metadata
- Authors
- Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X., & Delgoffe, G. M.
- Affiliations
- University of Pittsburgh (US)
- UPMC Hillman Cancer Center (US)
- Corresponding author
- Delgoffe, Greg M.
- Venue
- Cancer Immunology Research
- Published
- 2017-01-01
- Volume
- 5
- Issue
- 1
- Pages
- 9-16
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC5340074
- OpenAlex
- W2560185130
- Cited by
- 520
- References
- 30
- Citations by year
- 2026: 34 · 2025: 53 · 2024: 49 · 2023: 72 · 2022: 85 · 2021: 79 · 2020: 69 · 2019: 38 · 2018: 30 · 2017: 11
- FWCI
- 14.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- UPCI (P30CA047904)
- Sidney Kimmel Foundation for Cancer Research (SKF-015-039)
- University of Pittsburgh Cancer Institute Skin Cancer (P50CA121973-08)
- University of Pittsburgh Cancer Institute Head and Neck Cancer SPORE (P50 CA097190)
- Cancer-AACR Innovative Research (SU2C-AACR-IRG-04-16)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- anti-PD-1 therapy, metformin, tumor hypoxia, tumor microenvironment, cancer immunotherapy resistance, combination therapy, oxidative metabolism, T cell function, B16 melanoma, MC38 colon carcinoma, antitumor immunity
- MeSH terms
- Tumor Hypoxia, Antineoplastic Agents, Immunological, Animals, Cytotoxicity, Immunologic, Drug Synergism, Energy Metabolism, Melanoma, Experimental, Metformin, Oxygen Consumption, T-Lymphocytes, Cytokines, Lymphocytes, Tumor-Infiltrating, Mice, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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