Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors.
Biomarkers
Checkpoint inhibitors
Combination therapy
Drug resistance mechanisms in immunotherapy
Immune checkpoint inhibitors
Immune response
Immunotherapy
Modulators of tumor microenvironment
Oncology
Precision medicine
T-cells
pH modulation of the tumor microenvironment
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
15 Dec 2023
15 Dec 2023
Historique:
received:
14
04
2023
accepted:
12
11
2023
medline:
16
12
2023
pubmed:
16
12
2023
entrez:
16
12
2023
Statut:
epublish
Résumé
Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ
Identifiants
pubmed: 38102680
doi: 10.1186/s12943-023-01900-0
pii: 10.1186/s12943-023-01900-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
207Informations de copyright
© 2023. The Author(s).
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