title: Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma.
abstract: CD73 is a cell surface enzyme that suppresses T cell-mediated immune responses by producing extracellular adenosine. Growing evidence suggests that targeting CD73 in cancer may be useful for an effective therapeutic outcome. In this study, we demonstrate that administration of a specific CD73 inhibitor, adenosine 5'-(α,β-methylene)diphosphate (APCP), to melanoma-bearing mice induced a significant tumor regression by promoting the release of Th1- and Th17-associated cytokines in the tumor microenvironment. CD8+ T cells were increased in melanoma tissue of APCP-treated mice. Accordingly, in nude mice APCP failed to reduce tumor growth. Importantly, we observed that after APCP administration, the presence of B cells in the melanoma tissue was greater than that observed in control mice. This was associated with production of IgG2b within the melanoma. Depletion of CD20+ B cells partially blocked the anti-tumor effect of APCP and significantly reduced the production of IgG2b induced by APCP, implying a critical role for B cells in the anti-tumor activity of APCP. Our results also suggest that APCP could influence B cell activity to produce IgG through IL-17A, which significantly increased in the tumor tissue of APCP-treated mice. In support of this, we found that in melanoma-bearing mice receiving anti-IL-17A mAb, the anti-tumor effect of APCP was ablated. This correlated with a reduced capacity of APCP-treated mice to mount an effective immune response against melanoma, as neutralization of this cytokine significantly affected both the CD8+ T cell- and B cell-mediated responses. In conclusion, we demonstrate that both T cells and B cells play a pivotal role in the APCP-induced anti-tumor immune response.
authors: Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano, 84084 Salerno, Italy.
authors: Giovanni
authors: G
authors: Forte
authors: Rosalinda
authors: R
authors: Sorrentino
authors: Antonella
authors: A
authors: Montinaro
authors: Antonio
authors: A
authors: Luciano
authors: Ian M
authors: IM
authors: Adcock
authors: Piera
authors: P
authors: Maiolino
authors: Claudio
authors: C
authors: Arra
authors: Carla
authors: C
authors: Cicala
authors: Aldo
authors: A
authors: Pinto
authors: Silvana
authors: S
authors: Morello
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D000244:Adenosine Diphosphate; D015720:5'-Nucleotidase