title: Role of TGF-β signaling in generation of CD39+CD73+ myeloid cells in tumors.
abstract: There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and proangiogenic properties of myeloid cells. We have previously shown that the deletion of the TGF-β type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth, suggesting protumorigenic effect of TGF-β signaling. In this study, we tested the hypothesis that TGF-β drives differentiation of myeloid-derived suppressor cells into protumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell-surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from mice with spontaneous tumor formation of mammary gland and conditional deletion of the type II TGF-β receptor in mammary epithelium, an increased level of TGF-β protein was associated with further increase in number of CD39(+)CD73(+) TDMMCs compared with MMTV-PyMT/TGFβRII(WT) control tumors with intact TGF-β signaling. Using genetic and pharmacological approaches, we demonstrated that the TGF-β signaling mediates maturation of myeloid-derived suppressor cells into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGF-β signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels, and diminished progression of both Lewis lung carcinoma and spontaneous mammary carcinomas. We propose that TGF-β signaling can directly induce the generation of CD39(+)CD73(+) TDMMCs, thus contributing to the immunosuppressive, proangiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.
authors.affiliation: Cardiovascular Division, Department of Medicine, Vanderbilt University, Nashville, TN 37232; and sergey.v.novitskiy@vanderbilt.edu sergey.v.ryzhov@vanderbilt.edu.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ryzhov
authors.affiliation: Cancer Biology Department, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.affiliation: Cancer Biology Department, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.affiliation: Cancer Biology Department, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.affiliation: Cardiovascular Division, Department of Medicine, Vanderbilt University, Nashville, TN 37232; and.
authors.forename: Qinkun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Cancer Biology Department, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.affiliation: Cardiovascular Division, Department of Medicine, Vanderbilt University, Nashville, TN 37232; and.
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
authors.affiliation: Cancer Biology Department, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Cancer Biology Department, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232 sergey.v.novitskiy@vanderbilt.edu sergey.v.ryzhov@vanderbilt.edu.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
mesh_terms: D015720:5'-Nucleotidase / Q000096:biosynthesis*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001081:Apyrase / Q000096:biosynthesis*; D001854:Bone Marrow Cells / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D005260:Female; D008321:Mammary Glands, Animal / Q000166:cytology / Q000276:immunology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology*; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen