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 4

Differential effects of LDH inhibition in tumor cells compared with tumor-infiltrating T cells.

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Differential effects of LDH inhibition in tumor cells compared with tumo...
(A) Mice (n = 5/group) were implanted with B16-YFP cells and treated with LDHi (100 mg/kg) or vehicle control as indicated in the schematic (A). Tumors were processed for flow cytometry quantification of glucose-Cy3, GLUT1, and LDH (MFI) in YFP+ tumor cells (B) and (C–E) in tumor-infiltrating and spleen-derived CD8+, CD4+Foxp3–, and CD4+Foxp3+ T cells. For glucose-Cy3 staining for C, FOXP3–GFP C57BL/6J transgenic mice were used to identify Foxp3+CD4+ Tregs in live cells. (F) Representative flow cytometry histograms and quantified percentages of Ki67+ of B16-YFP+ cells and (G) representative flow cytometry histograms and quantified percentages of Ki67+ of tumor-infiltrating CD8+, CD4+Foxp3–, and CD4+Foxp3+ T cells from B16-YFP tumors implanted in mice (n = 5/group), as indicated in the schematic in A. (H) Representative flow cytometry contour plots of tumor-infiltrating CD8+ T cells stratified by high or low glucose-Cy3 uptake and (I) quantification of percentages of Cy3-high or -low out of total CD8+ T cells (n = 5). (J) Representative flow cytometry contour plots and quantified percentages of PD-1+ of tumor-infiltrating CD8+ T cells stratified by high or low glucose-Cy3 uptake. Data show a representative experiment of 3 independent experiments. All statistics produced by Wilcoxon’s rank-sum test implemented in GraphPad Prism. *P < 0.05; **P < 0.01; ****P < 0.0001. Data are represented as mean ± SEM.