Babl, Nathalie and Decking, Sonja-Maria and Voll, Florian and Althammer, Michael and Sala-Hojman, Ada and Ferretti, Roberta and Korf, Clarissa and Schmidl, Christian and Schmidleithner, Lisa and Nerb, Benedikt and Matos, Carina and Koehl, Gudrun E. and Siska, Peter and Bruss, Christina and Kellermeier, Fabian and Dettmer, Katja and Oefner, Peter J. and Wichland, Marvin and Ugele, Ines and Bohr, Christopher and Herr, Wolfgang and Ramaswamy, Shivapriya and Heinrich, Timo and Herhaus, Christian and Kreutz, Marina and Renner, Kathrin (2023) MCT4 blockade increases the efficacy of immune checkpoint blockade. JOURNAL FOR IMMUNOTHERAPY OF CANCER, 11 (10): e007349. ISSN , 2051-1426
Full text not available from this repository. (Request a copy)Abstract
Background & AimsIntratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.MethodsTo determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1).ResultsInhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact.ConclusionsThese findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MONOCARBOXYLATE TRANSPORTER 4; TUMOR-ASSOCIATED MACROPHAGES; T-CELL METABOLISM; COLORECTAL-CANCER; PATIENT SURVIVAL; LYMPHOCYTES; GLYCOLYSIS; EXPRESSION; GLUCOSE; IMMUNOSCORE; Tumor Microenvironment; Lymphocytes, Tumor-Infiltrating; Immune Checkpoint Inhibitors; Drug Therapy, Combination; Immunologic Surveillance; Metabolism |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Hals-Nasen-Ohren-Heilkunde Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Mar 2024 15:15 |
| Last Modified: | 07 Mar 2024 15:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58953 |
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