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

• DOI: 10.1038/s43018-022-00470-2
• Publication Date: 2022-12-15T17:04:04Z
• Authors: 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
• Keywords: Immunosuppression

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 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed epithelial cells. Functionally, SLC4A4 inhibition PDAC cells mitigates acidosis of TME due to accumulation extracellular space a decrease lactate production result reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological targeting improves T cell-mediated response breaches macrophage-mediated immunosuppression, thus inhibiting growth metastases. addition, Slc4a4 combination checkpoint blockade is able overcome immunotherapy prolong survival. Overall, our data propose therapeutic target unleash antitumor PDAC.