Cancer letters, 2021-12, Vol.522, p.80-92
2021
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- Autor(en) / Beteiligte
- Titel
- Plasmacytoid dendritic cells recruited by HIF-1α/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma
- Ist Teil von
- Cancer letters, 2021-12, Vol.522, p.80-92
- Ort / Verlag
- Ireland: Elsevier B.V
- Erscheinungsjahr
- 2021
- Quelle
- Elsevier ScienceDirect Journals
- Beschreibungen/Notizen
- Plasmacytoid dendritic cells (pDCs) play immunosuppressive roles in the tumor microenvironment (TME). However, the molecular mechanisms underlying the recruitment and dysfunction of pDCs in the TME remain largely elusive, especially in hepatocellular carcinoma (HCC). In this study, we observed the accumulation of pDCs in the blood, tumor tissue, and ascitic fluid of HCC patients. A high density of tumor-infiltrating pDCs was correlated with poor prognosis in patients with HCC. Hypoxia-induced extracellular adenosine (eADO) significantly enhanced pDC recruitment into tumors via the adenosine A1 receptor (ADORA1). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transcriptionally upregulated the expression of the ectonucleotidases CD39 and CD73 in HCC cells, both of which are essential for the generation of eADO. Moreover, eADO-stimulated pDCs promoted the induction of regulatory T cells and suppressed proliferation and cytotoxicity of CD8+ T cells. Depletion of pDCs using a monoclonal antibody or an ADORA1 antagonist significantly improved antitumor immunity and suppressed HCC growth in the immunocompetent HCC mouse model. Thus, targeting pDC recruitment may serve as a potential adjuvant strategy for immunotherapies in HCC. •Tumor-derived extracellular adenosine (eADO) promoted pDC accumulation in HCC via adenosine A1 receptor.•HIF-1α upregulated the expression of ectonucleotidases CD39 andCD73, both of which are essential for the generation of eADO.•eADO-stimulated pDCs promoted the expansion of regulatory T cells and the exhaustion of CD8+ T cell.•Depletion of pDCs enhanced antitumor immunity and suppressed tumor growth.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0304-3835eISSN: 1872-7980DOI: 10.1016/j.canlet.2021.09.022Titel-ID: cdi_proquest_miscellaneous_2574407801
- Format
- –
- Schlagworte
- 5'-Nucleotidase - genetics, Ablation, Adenosine, Adenosinergic signaling pathway, Animals, Antibodies, Monoclonal - pharmacology, Antigens, CD - genetics, Apyrase - genetics, Ascitic fluid, Ascitic Fluid - immunology, Carcinoma, Hepatocellular - genetics, Carcinoma, Hepatocellular - immunology, Carcinoma, Hepatocellular - pathology, CD73 antigen, CD8 antigen, CD8-Positive T-Lymphocytes - immunology, Cell Line, Tumor, Cell proliferation, Cell Proliferation - genetics, Cytotoxicity, Dendritic cells, Dendritic Cells - immunology, Dendritic Cells - pathology, Disease, ENTPD1/CD39, ET5E/CD73, Extracellular adenosine, Gene Expression Regulation, Neoplastic - immunology, Hepatocellular carcinoma, Heterografts, Humans, Hypoxia, Hypoxia-inducible factor 1, Hypoxia-Inducible Factor 1, alpha Subunit - genetics, Hypoxia-inducible factor 1a, Immunoregulation, Immunosuppression, Immunotherapy, Liver cancer, Liver Neoplasms - genetics, Liver Neoplasms - immunology, Liver Neoplasms - pathology, Lymphocytes, Lymphocytes T, Medical prognosis, Metabolism, Metabolites, Mice, Molecular modelling, Monoclonal antibodies, Receptor, Adenosine A1 - genetics, Survival analysis, T cell exhaustion, T-Lymphocytes, Cytotoxic - immunology, Tumor microenvironment, Tumor Microenvironment - immunology, Tumors