Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models
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
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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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 1

Differential expression of LDHA in tumor cells compared with T cells.

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Differential expression of LDHA in tumor cells compared with T cells. (A...
(A) Average LDHA RNA expression across the indicated human tissue types; lines on graph denote median gene expression in healthy tissue. Source: CCLE (n = 150) and GTEx (n = 80). (B) Comparison in LDHA RNA expression between the indicated normal and cancerous cell types of interest. (C) Quantified LDHA RNA expression from tumor-infiltrating CD8+ T cells versus malignant cells from human melanoma scRNA-Seq data. Source: Tirosh et al. (42) (n = 19). (D) Flow cytometry quantification of intracellular LDH (n = 3) and (E) ECAR by Seahorse in cultured SK-MEL-28 melanoma cells and activated T cells isolated from healthy donors. T cells were analyzed on day 3 after activation with anti-CD3/CD28 beads. Data show 1 representative experiment of 3 independent experiments (n = 12). (F) Flow cytometry quantification of intracellular LDH MFI and glucose-Cy3 MFI in tumor-infiltrating CD8+ T cells and tumor cells from established B16-YFP murine tumors as indicated in the schematic. Data show 1 representative experiment of 3 independent experiments (n = 6). (G) Correlation matrix between expression of the indicated genes related to immune cell activation and glycolysis in human melanoma cases from the TCGA (n = 400). All statistics produced by unpaired t tests with Welch’s correction implemented in GraphPad Prism. **P < 0.01; ****P < 0.0001. Data are represented as mean ± SEM.