293 Acidosis Promotes Immune Escape Through the IFN-γ-induced Induction of PD-L1 Transcription in Cancer Cells
Journal of Investigative Dermatology(2023)
摘要
In the tumor microenvironment (TME), the expression of programmed cell death ligand-1 (PD-L1) on cancer cells is mainly regulated by IFN-γ and induces T cell exhaustion, enabling tumor immune escape. Here, we show that acidosis, a frequent feature of solid tumors, significantly increased IFN-γ-induced PD-L1-expression on cancer cells. This phenomenon was mediated by increased genomic expression and phosphorylation of STAT1 and translation of the Stat1 mRNA by eukaryotic initiation factor 4F (elF4F). The acidosis-mediated increase in IFN-γ-induced PD-L1-expression was observed in anti-PD-L1-responsive MC38 and CT26 adenocarcinoma cells, but not in anti-PD-L1-nonresponsive B16-F10 melanoma or 4T1 mammary carcinoma cells. Neutralization of the acidic extracellular tumor pH (pHe) by sodium bicarbonate (NaHCO3) treatment suppressed IFN-γ-induced PD-L1-expression in both cultured MC38 cancer cells and MC38 tumors. In anti-PD-L1-responsive tumors, NaHCO3 treatment not only increased the tumor pHe but also increased immune cell infiltration and reduced tumor growth. In contrast, in anti-PD-L1-nonresponsive tumors, NaHCO3-mediated pHeneutralization did not modulate PD-L1-expression in the tumor and failed to reduce tumor volume. In summary, we propose an acidosis-mediated increase in IFN-γ-induced PD-L1-expression on cancer cells via enhanced STAT1 phosphorylation as an immune escape mechanism that might serve as a novel biomarker for the anti-PD-L1/PD-1 treatment response.
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