title: Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma.
abstract: Dasatinib (DAS) is a potent inhibitor of the BCR-ABL, SRC, c-KIT, PDGFR, and ephrin tyrosine kinases that has demonstrated only modest clinical efficacy in melanoma patients. Given reports suggesting that DAS enhances T cell infiltration into the tumor microenvironment, we analyzed whether therapy employing the combination of DAS plus dendritic cell (DC) vaccination would promote superior immunotherapeutic benefit against melanoma. Using a M05 (B16.OVA) melanoma mouse model, we observed that a 7-day course of orally-administered DAS (0.1 mg/day) combined with a DC-based vaccine (VAC) against the OVA257-264peptide epitope more potently inhibited tumor growth and extended overall survival as compared with treatment with either single modality. The superior efficacy of the combinatorial treatment regimen included a reduction in hypoxic-signaling associated with reduced levels of immunosuppressive CD11b+Gr1+myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+regulatory T (Treg) populations in the melanoma microenvironment. Furthermore, DAS + VAC combined therapy upregulated expression of Type-1 T cell recruiting CXCR3 ligand chemokines in the tumor stroma correlating with activation and recruitment of Type-1, vaccine-induced CXCR3+CD8+tumor-infiltrating lymphocytes (TILs) and CD11c+DC into the tumor microenvironment. The culmination of this bimodal approach was a profound "spreading" in the repertoire of tumor-associated antigens recognized by CD8+TILs, in support of the therapeutic superiority of combined DAS + VAC immunotherapy in the melanoma setting.
authors.affiliation: Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA.
authors.forename: Devin B
authors.initials: DB
authors.lastname: Lowe
authors.affiliation: Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA.
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.affiliation: Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.affiliation: Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Tawbi
authors.affiliation: Department of Biostatistics; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.affiliation: Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; Department of Immunology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
keywords: Tregs; dasatinib; dendritic cell; melanoma; myeloid-derived suppressor cells; vaccine
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