MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC).

Autor: Wu, Qiulin, Li, Xicai, Yang, Yan, Huang, Jingquan, Yao, Ming, Li, Jianjun, Huang, Yubin, Cai, Xiaoyong, Geller, David A., Yan, Yihe
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Zdroj: Cancers; Jan2024, Vol. 16 Issue 2, p269, 18p
Abstrakt: Simple Summary: The effect of macrophages on tumor cells in the tumor microenvironment of hepatocellular carcinoma (HCC) has attracted more attention. In this study, expression levels of MMP9 and MICA were significantly elevated in macrophages and tumor cells, respectively. The IFN-γ pathway was activated in MICA+ tumor cells and MMP9+ macrophages. The interaction between MICA+ tumor cells and MMP9+ macrophages was mediated through the PROS1-AXL pathway. MMP9 was mainly expressed in M2-like macrophages. IRF1 induced the upregulation of PROS1 and MICA in HCC cells. MICA+ tumor cells stimulated the secretion of MMP9 from macrophages through the PROS1-AXL axis, thereby facilitating the proteolytic shedding of MICA into soluble MICA. This study provided valuable insights and supported the therapeutic application of AXL inhibition in HCC. Background: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. Methods: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. Results: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. Conclusion: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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