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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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“They demonstrated that the combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumour clearance in their experiments on murine tumour lines B16 and MC38 [483].”
Lee, J. J., & Chu, E. (2018) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2018.06.004 · Cited by 55
“cells in vivo, resulting in reduced intratumoral hypoxia, which then leads to enhanced antitumor activity of intratumoral T cells induced by PD-1 blockade in murine MC38 CRC models.(67)”
BackgroundMenon, D. R., Hammerlindl, H., Torrano, J., Schaider, H., & Fujita, M. (2020) · Theranostics · doi:10.7150/thno.42523 · Cited by 57
“This effect can be overcome by oxidative phosphorylation inhibitors such as metformin [141] that target metabolic adaptions to boost immunogenicity.”
BackgroundOXPHOS inhibitors, metabolism and targeted therapies in cancer
Cadassou, O., & Jordheim, L. P. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115531 · Cited by 59
Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment
Guan, Q., Han, M., Guo, Q., Yan, F., Wang, M., Ning, Q., & Xi, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1204363 · Cited by 57
“Increased the effects of PD1/PDL1 blockade; Melanoma (B16); Colon cancer (MC38) M PD1/PDL1 blockade (74)”
Background“Double-Edged Sword” Effect of Reactive Oxygen Species (ROS) in Tumor Development and Carcinogenesis
Zhao, W., Zhuang, P., Chen, Y., Wu, Y. L., Zhong, M., & Lun, Y. (2023) · Physiological Research · doi:10.33549/physiolres.935007 · Cited by 56
Akce, M., Farran, B., Switchenko, J. M., Rupji, M., Kang, S., Khalil, L. E., Ruggieri, A. N., Olson, B. M., Shaib, W. L., Wu, C. S.-Y., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007235 · Cited by 55
Bahrambeigi, S., & Shafiei‐Irannejad, V. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.113787 · Cited by 51
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“385 Moreover, inhibiting glycolysis while activating CD8 + T cells enhances the formation of long-lived memory T cells, which boosts their tumoricidal function.”
Yu, Y., Wang, S., Liu, Z., Zhang, X., Hu, Z., Dong, H.-J., Lu, X., Zheng, J.-B., & Cui, H. (2023) · Chinese Medicine · doi:10.1186/s13020-023-00751-7 · Cited by 49
“Hypoxia is another characteristic of TME that hinders ICI efficacy [49].”
BackgroundImmunometabolism in the Tumor Microenvironment
Roy, D. G., Kaymak, I., Williams, K. S., Ma, E. H., & Jones, R. G. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055817 · Cited by 49
Obesity-Associated Colorectal Cancer
Gonzalez-Gutierrez, L., Motiño, O., Barriuso, D., de la Puente-Aldea, J., Alvarez-Frutos, L., Kroemer, G., Palacios, R., & Senovilla, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168836 · Cited by 55
“Moreover, preclinical studies have shown that the combination of metformin with PD-1 blockade potentiates PD-1 blockade [264].”
BackgroundBeyond Cancer Cells: How the Tumor Microenvironment Drives Cancer Progression
Sabit, H., Arneth, B. M., Abdel-Ghany, S. E., Madyan, E. F., Ghaleb, A. H., Selvaraj, P., Shin, D. M., Bommireddy, R., & El-Hashash, A. H. K. (2024) · Cells · doi:10.3390/cells13191666 · Cited by 51
“Oxygen levels within tumors are often heterogeneous, leading to varied responses to immunotherapy across different tumor regions [27].”
BackgroundMetabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints
Xu, Y., He, L., Fu, Q., & Hu, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.759015 · Cited by 51
Modern Aspects of Immunotherapy with Checkpoint Inhibitors in Melanoma
Petrova, V., Arkhypov, I., Weber, R., Groth, C., Altevogt, P., Utikal, J. S., & Umansky, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072367 · Cited by 50
Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors
Liu, W., Wang, Y., Luo, J., Liu, M., & Luo, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.586760 · Cited by 46
Najafi, A., Keykhaee, M., Khorramdelazad, H., Karimi, M. Y., Samimi, L. N., Aghamohamadi, N., Karimi, M., Falak, R., & Khoobi, M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113483 · Cited by 48
Paidi, S. K., Troncoso, J. R., Raj, P., Diaz, P. M., Ivers, J. D., Lee, D. E., Avaritt, N. L., Gies, A. J., Quick, C. M., Byrum, S. D., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-1438 · Cited by 46
“Tumor microenvironment (TME) composition and metabolism have been shown to play important roles in the regulation of immune response and disease progression (20, 21).”
BackgroundCell metabolism-based optimization strategy of CAR-T cell function in cancer therapy
Li, W., Pan, X., Chen, L., Cui, H., Mo, S., Pan, Y., Shen, Y., Shi, M., Wu, J., Luo, F., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1186383 · Cited by 49
“Treatments targeting tumor cell oxidative metabolism can considerably sensitize some resistant cancers to checkpoint blockade (126, 127).”
Backgroundde Mey, S., Jiang, H., Corbet, C., Wang, H., Dufait, I., Ka, L. L., Bastien, E., Verovski, V. N., Gevaert, T., Féron, O., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01073 · Cited by 45
“Metformin and phenformin are indeed known to inhibit the activity of pro-tumor MDSC and macrophages, and to enhance the generation of anti-tumor memory CD8+T-cell, consequently improving the efficacy of anti-cancer vaccine and PD-1 blockade (Eikawa et al., 2015; Kim et al., 2017; Scharping et al., 2017).”
BackgroundCurry, J., Johnson, J. M., Mollaee, M., Tassone, P. T., Amin, D. R., Knops, A. M., Whitaker‐Menezes, D., Mahoney, M. G., South, A. P., Rodeck, U., et al. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00436 · Cited by 44
“Alternatively, the anticancer effects of metformin may be indirectly mediated through effects on other elements of the TME such as enhanced immune activity as seen in animal models of other tumor types (12).”
BackgroundInfluentialGulati, S., Desai, J. M., Palackdharry, S. M., Morris, J. C., Zhu, Z. G., Jandarov, R., Riaz, M. K., Takiar, V., Mierzwa, M. L., Gutkind, J. S., et al. (2019) · Cancer · doi:10.1002/cncr.32539 · Cited by 45
“The impact of metformin on the metabolic milieu of the tumor microenvironment, especially its ability to reduce the level of hypoxia, is of special interest and has been explored in preclinical studies.(11,12) This metabolic effect of metformin also is believed to be the mechanism by which the sensitivity of tumor tis…”
BackgroundLuo, L., Li, X., Zhang, J., Zhu, C., Jiang, M., Luo, Z., Qin, B., Wang, Y., Chen, B., Du, Y., et al. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.120678 · Cited by 44
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Wang, S., Zhou, X., Zeng, Z., Sui, M., Chen, L., Feng, C., Huang, C. Y., Yang, Q., Ji, M., & Hou, P. (2021) · Journal of Nanobiotechnology · doi:10.1186/s12951-021-01034-9 · Cited by 43
Ma, G., Li, C., Zhang, Z., Liang, Y., Liang, Z., Chen, Y., Wang, L., Li, D., Zeng, M., Shan, W., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.697894 · Cited by 45
“For example, metformin, which affects glucose metabolism and levels, reduced the hypoxic state of xenograft tumors, which rendered the tumors responsive to PD-1 blockade and enhancing the function of immune cells (75).”
BackgroundYuan, J. X., Li, Y., Zhang, H., Beeraka, N. M., Zhang, D., Wang, Q., Wang, M., Hemanth Vikram, P. R., Sethi, G., & Wang, G. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117714 · Cited by 47
RetractedTao, Y., Liu, Y., Dong, Z., Chen, X., Wang, Y., Li, T., Li, J., Zang, S., He, X., Chen, D., et al. (2022) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.2c10021 · Cited by 42
Key promoters of tumor hallmarks
Mortezaee, K., & Majidpoor, J. (2021) · International Journal of Clinical Oncology · doi:10.1007/s10147-021-02074-9 · Cited by 42
“The result of this recovered normality in tumor vessels is the adjustment or normalization of TME hypoxia [79, 80].”
BackgroundManipulating T-cell metabolism to enhance immunotherapy in solid tumor
Chen, C., Wang, Z., Ding, Y., & Qin, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1090429 · Cited by 43
“A strong evidence manifested that metformin and ICI have a synergistic effect to improve T-cell function and enhance tumor clearance (70).”
BackgroundMetabolic Traits in Cutaneous Melanoma
Neagu, M. T. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00851 · Cited by 43
“Tumor hypoxia Metformin Lowering tumor hypoxia (94)”
BackgroundKim, Y., Vagia, E., de Viveiros, P. A. H., Kang, C. Y., Lee, J. Y., Gim, G., Cho, S., Choi, H., Kim, L., Park, I., et al. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02703-8 · Cited by 42
Johnson, R. L., Cummings, M., Thangavelu, A., Theophilou, G., Jong, D. D., & Orsi, N. M. (2021) · Cancers · doi:10.3390/cancers13246231 · Cited by 39
Perspectives on Hypoxia Signaling in Tumor Stroma
Zhang, Y., Coleman, M., & Brekken, R. A. (2021) · Cancers · doi:10.3390/cancers13123070 · Cited by 39
Kheshtchin, N., & Hadjati, J. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30643 · Cited by 42
“In addition, emerging evidence revealed the opposing effect of hypoxia in immunotherapies (Hatfield et al., 2015; Jayaprakash et al., 2018; Martin et al., 2019; Scharping et al., 2017).”
BackgroundMetabolic advantages of regulatory T cells dictated by cancer cells
Kondo, M., Kumagai, S., & Nishikawa, H. (2023) · International Immunology · doi:10.1093/intimm/dxad035 · Cited by 42
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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