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

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).

Citation

Federica Cappellesso, Marie-Pauline Orban, Niranjan Shirgaonkar, Emanuele Berardi, Jens Serneels, Marie-Aline Neveu, Daria Di Molfetta, Francesca Piccapane, Rosa Caroppo, Lucantonio Debellis, Tessa Ostyn, Nicolas Joudiou, Lionel Mignion, Elena Richiardone, Bénédicte F Jordan, Bernard Gallez, Cyril Corbet, Tania Roskams, Ramanuj DasGupta, Sabine Tejpar, Mario Di Matteo, Daniela Taverna, Stephan J Reshkin, Baki Topal, Federico Virga, Massimiliano Mazzone. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. Nature cancer. 2022 Dec;3(12):1464-1483

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PMID: 36522548

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