Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors

Zafer Gurel; Michael S Luy; Qianyun Luo; Nicholas L Arp; Amy K Erbe; Aparna H Kesarwala; Jing Fan; Randall J Kimple

doi:10.3389/fonc.2024.1428802

Metabolic modulation of melanoma enhances the therapeutic potential of immune checkpoint inhibitors

Front Oncol. 2024 Oct 1:14:1428802. doi: 10.3389/fonc.2024.1428802. eCollection 2024.

Authors

Zafer Gurel¹, Michael S Luy¹, Qianyun Luo¹, Nicholas L Arp², Amy K Erbe¹, Aparna H Kesarwala³, Jing Fan^{2

4

5}, Randall J Kimple^{1

6}

Affiliations

¹ Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
² Morgridge Institute for Research, Madison, WI, United States.
³ Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United States.
⁴ Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, United States.
⁵ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States.
⁶ University of Wisconsin (UW) Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.

Abstract

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: LDH; NHI-2; cancer metabolism; immune checkpoint inhibitors; lactate; melanoma; oxamate.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors acknowledge support from the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520 (RK), the University of Wisconsin Head and Neck SPORE Grant P50 DE026787 (RK), the University of Wisconsin Institute for Clinical and Translational Research 1UL1TR002373 (RK), and the Melanoma Research Alliance 695862 (AK).