期刊
ONCOIMMUNOLOGY
卷 3, 期 2, 页码 -出版社
LANDES BIOSCIENCE
DOI: 10.4161/onci.27589
关键词
dasatinib; vaccine; dendritic cell; melanoma; myeloid-derived suppressor cells; Tregs
资金
- NIH [R01s CA143075, CA169118, P50 CA121973]
- University of Pittsburgh Cancer Center Support Grant (CCSG) [P30 CA047904]
- American Cancer Society [PF-11-151-01-LIB]
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 OVA(257-264) peptide 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(+)Foxp(3+) regulatory T (Treg) populations in the melanoma microenvironment. Furthermore, DAS + VAC combined therapy upregulated expression of Type-1 T cell recruiting CXCR 3 ligand chemokines in the tumor stroma correlating with activation and recruitment of Type-1, vaccine-induced CXCR3(+)CD8(+) tumor-infiltrating lymphocytes (TIL s) 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(+) TIL s, in support of the therapeutic superiority of combined DAS + VAC immunotherapy in the melanoma setting.
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