Unknown

Dataset Information

0

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 OVA257-264 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+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.

SUBMITTER: Lowe DB 

PROVIDER: S-EPMC3984268 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications

Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma.

Lowe Devin B DB   Bose Anamika A   Taylor Jennifer L JL   Tawbi Hussein H   Lin Yan Y   Kirkwood John M JM   Storkus Walter J WJ  

Oncoimmunology 20140101 1


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  ...[more]

Similar Datasets

| S-EPMC4514042 | biostudies-literature
| S-EPMC5084999 | biostudies-literature
| S-EPMC2765061 | biostudies-literature
| S-EPMC5007966 | biostudies-literature
| S-EPMC4760342 | biostudies-literature
| S-EPMC6794451 | biostudies-literature
| S-EPMC4957162 | biostudies-literature
| S-EPMC11304315 | biostudies-literature
| 2101939 | ecrin-mdr-crc
| S-EPMC5653516 | biostudies-literature