apyrase and Carcinoma--Hepatocellular

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

Topics: 5'-Nucleotidase; Animals; Antibodies, Monoclonal; Antigens, CD; Apyrase; Ascitic Fluid; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Dendritic Cells; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Mice; Receptor, Adenosine A1; T-Lymphocytes, Cytotoxic; Tumor Microenvironment

It remains controversial whether tumour mutational burden (TMB) or neoantigens are prognostic markers in hepatocellular carcinoma (HCC). This study aimed to define the function of TMB or neoantigens in antitumour immunotherapy.. The value of HAN showed a better correlation with OS (. Our study first demonstrates that HAN value positively correlates with better OS in patients with HCC. HANs trigger antitumour activity by activating tumour-reactive CD39

Topics: Algorithms; Antigens, Neoplasm; Apyrase; Biomarkers, Tumor; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Organoids; Prognosis

CD39, expressed by tumor-infiltrating lymphocytes (TILs), is a marker to identify tumor-reactive T cells, which is frequently associated with stronger antitumor activity than bystander T cells in a variety of malignancies. Therefore, CD39 could be a promising marker for identifying the active antitumor immune cells used for cellular immunotherapy. To test this possibility, we constructed the hepatitis B virus (HBV) surface protein-specific chimeric antigen receptor T cells (HBVs-CAR-T cells) and generated the personalized tumor-reactive CD8

Topics: Animals; Antigens, CD; Apyrase; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Coculture Techniques; Combined Modality Therapy; Gene Knockdown Techniques; Hep G2 Cells; Hepatitis A Virus Cellular Receptor 2; Hepatitis B virus; Humans; Interferon-gamma; Liver Neoplasms; Lymphocyte Activation Gene 3 Protein; Mice; Organoids; Programmed Cell Death 1 Receptor; Receptors, Antigen, T-Cell; RNA, Small Interfering; Xenograft Model Antitumor Assays

Topics: Animals; Apyrase; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Cellular Senescence; DNA-Binding Proteins; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mutation; RNA, Small Interfering; Transcription Factors

Nucleoside triphosphate diphosphohydrolase-1 (ENTPD1/CD39) is the rate-limiting enzyme in a cascade leading to the generation of immunosuppressive adenosine and plays an important role in tumor progression. This study aimed to evaluate the expression of CD39 and CD39Foxp3 regulatory T cells (Tregs) and to determine their prognostic role in patients with hepatocellular carcinoma (HCC) after radical resection.Immunohistochemistry (IHC) and double IHC were used to analyze CD39 expression or the expression of CD39 and Foxp3 in a cohort of 324 HCC patients who underwent curative resection. The quantification of CD39 expression levels was determined using a computerized image analysis system and was evaluated by mean optical density (MOD), which corresponded to the positive staining intensity of CD39. The number of positive Foxp3 cells and both CD39 and Foxp3 positive cells in each 1-mm-diameter cylinder were counted under high-power magnification (×400). The "minimum P value" approach was used to obtain the optimal cutoff value for the best separation between groups of patients in relation to time to recurrence (TTR) or overall survival (OS). The expression of CD39 in HCC cell lines with stepwise metastatic potential and in human umbilical vein endothelial cells was determined by reverse transcription-polymerase chain reaction, Western blotting, and immunofluorescence. The SPSS 17.0 statistical package was used for statistics.CD39 was principally expressed on vascular endothelial cells, macrophagocytes, Tregs, and tumor cells in HCC. Compared with paired peritumoral tissues, tumoral tissues had a significantly higher expression level of CD39 (P < 0.0001). Overexpression of tumoral CD39 was related to increased tumor recurrence and shortened overall survival. Furthermore, the expression level of peritumoral CD39 showed a prognostic role in TTR and OS. Double IHC showed that tumoral tissues had significantly higher Foxp3Tregs and CD39Foxp3Tregs count per 1 mm core (14.1659 vs 4.9877, P = 0.001; 11.5254 vs 3.3930, P < 0.001) and a higher CD39Foxp3/Foxp3 ratio compared with paired peritumoral tissues. CD39Foxp3Tregs were a better prognosticator than CD39Tregs for TTR.Overexpression of CD39 protein in HCC was an independent predictor of poor outcome after radical resection. The CD39Foxp3Tregs count added prognostic power to Foxp3Tregs, providing a potential target for tumor immunotherapy.

Topics: Antigens, CD; Apyrase; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Forkhead Transcription Factors; Hepatectomy; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; T-Lymphocytes, Regulatory

Liver cancer is associated with chronic inflammation, which is linked to immune dysregulation, disordered metabolism, and aberrant cell proliferation. Nucleoside triphosphate diphosphohydrolase-1; (CD39/ENTPD1) is an ectonucleotidase that regulates extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimately generate adenosine. These properties inhibit antitumor immune responses and promote angiogenesis, being permissive for the growth of transplanted tumors. Here we show that Cd39 deletion promotes development of both induced and spontaneous autochthonous liver cancer in mice. Loss of Cd39 results in higher concentrations of extracellular nucleotides, which stimulate proliferation of hepatocytes, abrogate autophagy, and disrupt glycolytic metabolism. Constitutive activation of Ras-mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR)-S6K1 pathways occurs in both quiescent Cd39 null hepatocytes in vitro and liver tissues in vivo. Exogenous adenosine 5'-triphosphate (ATP) boosts these signaling pathways, whereas rapamycin inhibits such aberrant responses in hepatocytes.. Deletion of Cd39 and resulting changes in disordered purinergic signaling perturb hepatocellular metabolic/proliferative responses, paradoxically resulting in malignant transformation. These findings might impact adjunctive therapies for cancer. Our studies indicate that the biology of autochthonous and transplanted tumors is quite distinct.

Topics: Animals; Antigens, CD; Apyrase; Autophagy; Carcinoma, Hepatocellular; Cell Proliferation; Gene Deletion; Gene Expression Regulation, Neoplastic; Glycolysis; Hepatocytes; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Receptors, Purinergic; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adenosine Triphosphate; Animals; Apyrase; Carcinoma, Hepatocellular; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Neoplasms; Phosphoric Monoester Hydrolases; Rats