Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
05
11
2021
accepted:
21
10
2022
pubmed:
16
12
2022
medline:
23
12
2022
entrez:
15
12
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36522548
doi: 10.1038/s43018-022-00470-2
pii: 10.1038/s43018-022-00470-2
pmc: PMC9767871
doi:
Substances chimiques
Bicarbonates
0
Sodium-Bicarbonate Symporters
0
Slc4a4 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1464-1483Subventions
Organisme : European Research Council
ID : 101069459
Pays : International
Organisme : European Research Council
ID : 773208
Pays : International
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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