Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer.

Autor: Cappellesso F; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Orban MP; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Shirgaonkar N; Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore., Berardi E; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Serneels J; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Neveu MA; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Di Molfetta D; Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy., Piccapane F; Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy., Caroppo R; Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy., Debellis L; Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy., Ostyn T; Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium., Joudiou N; Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium., Mignion L; Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium.; Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium., Richiardone E; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérmentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium., Jordan BF; Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium.; Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium., Gallez B; Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium.; Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium., Corbet C; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérmentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium., Roskams T; Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium., DasGupta R; Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore., Tejpar S; Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium., Di Matteo M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium., Taverna D; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Molecular Biotechnology Center, University of Torino, Torino, Italy., Reshkin SJ; Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy., Topal B; Department of Abdominal Surgery, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium., Virga F; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Molecular Biotechnology Center, University of Torino, Torino, Italy., Mazzone M; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium. massimiliano.mazzone@kuleuven.vib.be.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. massimiliano.mazzone@kuleuven.vib.be.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2022 Dec; Vol. 3 (12), pp. 1464-1483. Date of Electronic Publication: 2022 Dec 15.
DOI: 10.1038/s43018-022-00470-2
Abstrakt: Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member 4 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed by epithelial ductal cells. Functionally, SLC4A4 inhibition in PDAC cancer cells mitigates the acidosis of the TME due to bicarbonate accumulation in the extracellular space and a decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and breaches macrophage-mediated immunosuppression, thus inhibiting tumor growth and metastases. In addition, Slc4a4 targeting in combination with immune checkpoint blockade is able to overcome immunotherapy resistance and prolong survival. Overall, our data propose SLC4A4 as a therapeutic target to unleash an antitumor immune response in PDAC.
(© 2022. The Author(s).)
Databáze: MEDLINE
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