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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Cancer Metabolism
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1428802
This article is part of the Research Topic Metabolic Crosstalk between Cancer Cells and Immune Cells in the Tumor Microenvironment: Cellular and Molecular Insights, and their Therapeutic Implications View all 7 articles

Metabolic Modulation of Melanoma Tumors Enhances the Therapeutic Potential of Immune Checkpoint Inhibitors

Provisionally accepted
Zafer Gurel Zafer Gurel 1Michael S. Luy Michael S. Luy 1Qianyun Luo Qianyun Luo 1Nicholas L. Arp Nicholas L. Arp 2Amy Erbe Amy Erbe 1Aparna Kesarwala Aparna Kesarwala 3Jing Fan Jing Fan 2,4,5Randall Kimple Randall Kimple 1,6*
  • 1 University of Wisconsin-Madison, Madison, United States
  • 2 Morgridge Institute for Research, Madison, Wisconsin, United States
  • 3 Emory University, Atlanta, Georgia, United States
  • 4 Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, United States
  • 5 Department of Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, United States
  • 6 Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States

The final, formatted version of the article will be published soon.

    Introduction: Lactate is a pivotal molecule with diverse functions in the metabolic reprogramming of cancer cells. Beyond its role in metabolism, lactate exerts a modulatory effect within the tumor microenvironment; it is utilized by stromal cells and has been implicated in the suppression of the immune response against the tumor. Methods: Using in vitro assays (including flow cytometry, live-cell imaging and metabolic analyses), the impact of lactate dehydrogenase inhibitors (LDHIs) on melanoma cells were assessed. The therapeutic potential of LDHIs with immune checkpoint inhibitors (ICIs) were tested in vivo in murine models of melanoma tumors. Results: A potent anti-proliferative effect (via both cell cycle alterations and enhanced apoptosis) of LDHIs, Oxamate (Oxa) and methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2), was found upon treatment of melanoma cell lines. Using a combination of Oxa and NHI-2, a synergistic effect to inhibit proliferation, glycolysis, and ATP production was observed. Metabolic analysis revealed significant alteration in glycolysis and oxidative phosphorylation, while metabolite profiling emphasized consequential effects on lactate metabolism and induced energy depletion by LDHIs. Detection of increased RANTES and MCP-1, with Oxa and NHI-2 treatment, prompted the consideration of combining LDHIs with ICIs. In vivo studies using a murine B78 melanoma tumor model revealed a significant improvement in treatment efficacy when LDHIs were combined with ICIs.Conclusions: These findings propose the potential of targeting lactate metabolism to enhance the efficacy of ICI treatments in patients with melanoma.

    Keywords: Melanoma, Cancer Metabolism, Lactate, LDH, Oxamate, NHI-2, immune checkpoint inhibitors

    Received: 07 May 2024; Accepted: 10 Sep 2024.

    Copyright: © 2024 Gurel, Luy, Luo, Arp, Erbe, Kesarwala, Fan and Kimple. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Randall Kimple, University of Wisconsin-Madison, Madison, United States

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