Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models
Svena Verma, … , Jedd D. Wolchok, Taha Merghoub
Svena Verma, … , Jedd D. Wolchok, Taha Merghoub
Published September 3, 2024
Citation Information: J Clin Invest. 2024;134(17):e177606. https://doi.org/10.1172/JCI177606.
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Research Article Immunology Metabolism

Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models

Abstract

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Authors

Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M. Mangarin, Jonathan F. Khan, Mamadou A. Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D. Wolchok, Taha Merghoub

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Figure 2

LDHi reduces tumor glycolysis and progression.

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LDHi reduces tumor glycolysis and progression. (A) B16 viability and LDH...
(A) B16 viability and LDH activity 24 hours after treatment with GNE-140 (LDHi) at the indicated concentrations (n = 6). (B) Extracellular lactate and glucose from B16 cells treated with 10 μM LDHi or control vehicle for 24 hours, normalized by cell number (n = 3–5). (C) Extracellular acidification (ECAR) and OCRs of B16 cells treated with 10 μM LDHi or vehicle control for 24 hours, measured by Seahorse assays (glycolysis stress test and mitochondrial stress test). Data are normalized by cell number (n = 10). (D–F) Intracellular glycolysis. (E and F) TCA metabolites quantified by liquid chromatography–mass spectrometry (LC-MS) from B16 whole-cell lysates treated with 10 μM LDHi or vehicle control for 24 hours (n = 3–6). (G and H) Quantification of serum and tumor LDH activity from B16-bearing mice treated with 100 mg/kg LDHi or vehicle control (daily, p.o.) for 2 weeks, as indicated in the schematic (n = 5 mice/group). Sera and tumor lactate and LDH activity were analyzed 24 hours after the last treatment with LDHi. (I–K) Tumor growth curves of B16 or B16 LDHA KD in the indicated mouse strains treated with 100 mg/kg LDHi or vehicle control (daily, p.o.) for 2 weeks as indicated in the schematic (n = 10 mice/group). All data show 1 representative experiment of 3 independent experiments. All statistics produced by (B, E, and F) unpaired t tests with Welch’s correction or (C and I) 2-way ANOVA with Bonferroni’s multiple-comparisons test implemented in GraphPad Prism. *P < 0.05; **P < 0.01; ****P < 0.0001. Data are represented as mean ± SEM.