Targeting the Bicarbonate Transporter SLC4A4 Overcomes Immunosuppression and Immunotherapy Resistance in Pancreatic Cancer

Overview

Journal Nat Cancer

Specialty Oncology

Date 2022 Dec 15

PMID 36522548

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

Benedicte 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

Affiliations

Soon will be listed here.

Abstract

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.

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