title: BAFF and APRIL from Activin A-Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo.
abstract: The members of the TGFβ superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization, and survival of different cell types. Although the role of TGFβ1 in inflammation and immunity is well evident, the contribution of other TGFβ family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI. In vivo, activin A-stimulated DCs demonstrate a significantly increased ability to induce tumor-specific CTLs and inhibit the growth of melanoma and lung carcinoma, which relies on DC-derived BAFF and APRIL, as knockdown of the BAFF and APRIL gene expression in activin A-treated DCs blocks augmentation of their antitumor potential. Although systemic administration of activin A, BAFF, or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and nonmalignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pretreated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction. Cancer Res; 76(17); 4959-69. ©2016 AACR.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Shurin
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Anton A
authors.initials: AA
authors.lastname: Keskinov
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Ruijing
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Anna
authors.initials: A
authors.lastname: Lokshin
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Marianna
authors.initials: M
authors.lastname: Agassandian
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. shuringv@upmc.edu.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Shurin
mesh_terms: D028341:Activins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D053264:B-Cell Activating Factor / Q000096:biosynthesis* / Q000276:immunology; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000096:biosynthesis* / Q000276:immunology; D015854:Up-Regulation
chemical_list: D053264:B-Cell Activating Factor; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C422405:activin A; D028341:Activins