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

Although new immunotherapy approaches are efficient in different cancer types, Pancreatic adenocarcinoma (PDAC) tumors remain resistant. These tumors are characterized by a dense desmoplastic stroma that impedes oxygen and nutrient diffusion from the blood stream to the stroma and contributes to a strongly hypoxic and acidic tumor microenvironment (TME). A lot of research has been performed on the contribution of acidity to tumor progression and immunotherapy resistance. However, the role of bicarbonate transporters has been mostly neglected. Our aim was to study the impact of these transporters on the modulation of extracellular pH in the TME and on the anti-tumor immune response.

By single-cell RNA-sequencing analysis in PDAC patients, we reveal hereby 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 decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological targeting of SLC4A4 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 anti-tumor immune response in PDAC.