Myeloid Suppressor Cells Drive HCC Invasiveness via the THBS1-SDC4 Pathway.
TL;DR
This study provides mechanistic insight into how M-MDSCs are activated within the HCC tumor microenvironment and subsequently drive tumor cell EMT through THBS1-SDC4 signaling, and indicates the THBS1-SDC4 axis may represent a therapeutically targetable pathway to restrain M-MDSC-mediated tumor aggressiveness and modulate the tumor microenvironment.
Abstract
Background
&
Aims
Monocytic myeloid-derived suppressor cells (M-MDSCs) accumulate in hepatocellular carcinoma (HCC), but their activation and tumor-promoting mechanisms remain unclear. We investigated how stromal-myeloid-tumor crosstalk promotes HCC invasiveness and epithelial-mesenchymal transition (EMT).
Methods
We analyzed single-cell RNA-sequencing data from 36 HCC patients and spatial transcriptomics data from 2 HCC specimens to characterize M-MDSC localization and intercellular signaling. Matrix cancer-associated fibroblast and M-MDSC phenotypes and interactions were assessed using molecular and functional assays. Thrombospondin-1-syndecan-4 signaling was investigated in xenografts in immunodeficient mice (n = 8/group) and diethylnitrosamine/carbon tetrachloride-induced HCC in the immunocompetent mice (n = 6/group).
Results
M-MDSCs preferentially localized to EMT-active tumor margins and correlated with EMT activity (Spearman r = 0.30; false discovery rate = 3.3 × 10-4) and shorter overall survival (log-rank P = 0.00124). Matrix cancer-associated fibroblasts promoted M-MDSC activation through collagen-associated CD44 signaling. Activated M-MDSCs induced EMT through thrombospondin-1-syndecan-4 signaling, whereas syndecan-4 deficiency suppressed tumor cell proliferation, migration, invasion, and EMT. Thrombospondin-1-deficient M-MDSCs reduced xenograft progression and increased interferon-γ-positive CD8+ T-cell infiltration and cytotoxic immune markers in immunocompetent HCC. A thrombospondin communication pathway score was associated with shorter overall survival (log-rank P = 2.28 × 10-5; Cox hazard ratio = 1.23, P = 0.0193).
Conclusions
Matrix cancer-associated fibroblasts promote monocytic myeloid-derived suppressor cell activation, driving epithelial-mesenchymal transition in hepatocellular carcinoma through thrombospondin-1-syndecan-4 signaling. Targeting this axis may restrain tumor progression and enhance antitumor immunity. IMPACT AND IMPLICATIONS This study provides mechanistic insight into how M-MDSCs are activated within the HCC tumor microenvironment and subsequently drive tumor cell EMT through THBS1-SDC4 signaling. These findings highlight the importance of tumor-immune-stromal crosstalk in HCC progression and provide a mechanistic framework for understanding the pro-tumor functions of M-MDSCs. The THBS1-SDC4 axis may represent a therapeutically targetable pathway to restrain M-MDSC-mediated tumor aggressiveness and modulate the tumor microenvironment. Further validation in independent clinical cohorts and assessment of therapeutic efficacy are warranted to determine its translational potential.