Supporting data for "The roles of plasmacytoid dendritic cells on the tumor immune microenvironment and surgical stress-induced tumor recurrence in hepatocellular carcinoma"

Plasmacytoid dendritic cells (pDCs), a unique subset of dendritic cells, play immunosuppressive roles in the tumor microenvironment. However, the molecular mechanisms underlying pDC dysfunction in tumor microenvironment remain largely elusive, especially in hepatocellular carcinoma (HCC). In this study, we observed pDCs accumulated in tumor tissue and ascitic fluid of the patients with HCC. A high density of tumor-infiltrating pDCs (TI-pDCs), which exhibiting immature and immunosuppressive phenotype, was correlated with poor prognosis in HCC patients underwent curative hepatectomy. Hypoxia-induced extracellular adenosine (eADO) profoundly enhanced pDC recruitment into tumors via adenosine A1 receptor (ADORA1). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transcriptionally up-regulated the expression of ectonucleotidases ENTPD1 (CD39) and NT5E (CD73) in HCC cells, where both enzymes are essential for the generation of eADO. Moreover, gene expression profile of pDCs was changed markedly in the presence of eADO. eADO-stimulated pDCs promoted Foxp3 expression in naive CD4⁺ T cells and suppressed the proliferation and cytokine production (TNF-α, IFN-γ) of CD8⁺ T cells. Depletion of pDCs by a monoclonal antibody (anti-mPDCA-1, 120G8) or ADORA1 antagonist (DPCPX) significantly improved anti-tumor immunity and suppressed HCC growth in an immunocompetent HCC mouse model. Thus, targeting pDC recruitment may serve as a potential adjuvant strategy to immunotherapies of HCC.