MCT4 blockade increases the efficacy of immune checkpoint blockade
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Published:2023-10
Issue:10
Volume:11
Page:e007349
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ISSN:2051-1426
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Container-title:Journal for ImmunoTherapy of Cancer
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language:en
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Short-container-title:J Immunother Cancer
Author:
Babl NathalieORCID, Decking Sonja-Maria, Voll Florian, Althammer Michael, Sala-Hojman Ada, Ferretti Roberta, Korf Clarissa, Schmidl Christian, Schmidleithner Lisa, Nerb Benedikt, Matos Carina, Koehl Gudrun E, Siska PeterORCID, Bruss Christina, Kellermeier Fabian, Dettmer Katja, Oefner Peter J, Wichland Marvin, Ugele Ines, Bohr Christopher, Herr Wolfgang, Ramaswamy Shivapriya, Heinrich Timo, Herhaus Christian, Kreutz Marina, Renner Kathrin
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.
Funder
Merck KGaA, Darmstadt, Germany Leibniz Institute for Immunotherapy Regensburg Else Kröner-Fresenius-Foundation
Subject
Cancer Research,Pharmacology,Oncology,Molecular Medicine,Immunology,Immunology and Allergy
Cited by
1 articles.
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