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.
背景：在肝细胞癌（HCC）复杂的肿瘤微环境（TME）中，肿瘤相关巨噬细胞（TAMs）构成了非癌细胞的重要组成部分。理解巨噬细胞与肿瘤细胞之间的通讯，并探究潜在的信号通路，有望提升HCC的治疗反应。方法：单细胞RNA测序数据和大块组织RNA测序数据来源于开源数据库基因表达综合库（GEO）和癌症基因组图谱（TCGA）。通过分析，我们阐明了在晚期HCC中，MICA+肿瘤细胞与MMP9+巨噬细胞之间主要通过PROS1-AXL轴介导的相互作用。随后，我们采用了一系列实验技术，包括慢病毒感染、重组蛋白刺激和AXL抑制实验，以验证这些相互作用并揭示其潜在机制。结果：我们呈现了晚期HCC的单细胞图谱，分别突出了MICA在肿瘤细胞和MMP9在巨噬细胞中的表达模式。在MICA+肿瘤细胞和MMP9+巨噬细胞中观察到干扰素γ（IFN-γ）信号通路的激活。我们确定了MICA+肿瘤细胞与MMP9+巨噬细胞之间通过PROS1-AXL轴介导的相互作用的存在。此外，我们发现MMP9+巨噬细胞与M2样巨噬细胞呈正相关。随后的实验证实，DNA损伤不仅通过IRF1诱导肿瘤细胞中MICA的表达，还上调了HCC细胞中PROS1的水平，从而刺激巨噬细胞分泌MMP9。因此，MMP9导致了MICA的蛋白水解。结论：MICA+ HCC细胞分泌的PROS1通过AXL受体上调巨噬细胞中MMP9的表达。MMP9活性的增加导致MICA发生蛋白水解性脱落，释放出可溶性MICA（sMICA），进而促进肿瘤免疫逃逸。
肿瘤(癌症)患者之家