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Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2024 Sep 03; Vol. 134 (17). Date of Electronic Publication: 2024 Sep 03. - Publication Year :
- 2024
-
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.
- Subjects :
- Animals
Mice
Humans
Glucose Transporter Type 1 metabolism
Glucose Transporter Type 1 antagonists & inhibitors
Glucose Transporter Type 1 immunology
Glucose Transporter Type 1 genetics
Cell Line, Tumor
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory drug effects
Melanoma, Experimental immunology
Melanoma, Experimental pathology
Melanoma, Experimental drug therapy
Melanoma, Experimental metabolism
Glycolysis drug effects
Female
Lymphocytes, Tumor-Infiltrating immunology
Lymphocytes, Tumor-Infiltrating drug effects
Colonic Neoplasms immunology
Colonic Neoplasms drug therapy
Colonic Neoplasms pathology
Colonic Neoplasms metabolism
Enzyme Inhibitors pharmacology
Immunotherapy
Immune Checkpoint Inhibitors pharmacology
Immune Checkpoint Inhibitors therapeutic use
Glucose metabolism
Tumor Microenvironment immunology
Tumor Microenvironment drug effects
L-Lactate Dehydrogenase metabolism
L-Lactate Dehydrogenase antagonists & inhibitors
L-Lactate Dehydrogenase immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 134
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 39225102
- Full Text :
- https://doi.org/10.1172/JCI177606