Dasatinib (DAS) is an FDA-approved inhibitor of receptor tyrosine kinases (RTKs) (i.e., EphA2 and PDGFRβ) involved in vasculature development/maintenance of solid cancers such as melanoma. Administration of DAS transiently normalizes tumor blood vessels and reduces lesional interstitial pressure, hypoxia, and acidosis (which typically impede the efficacy of standard of care therapies). We hypothesized that DAS-induced vascular changes would lead to improved recruitment of therapeutic effector T cells, particularly after specific vaccination. As a model system, C57BL/6 mice bearing established day 7 subcutaneous B16 melanomas were vaccinated (weekly x 2; VAC) with a tumor-specific DC-based vaccine +/- DAS (i.p. daily for days 7-13). We confirmed that DAS reconditioned tumor blood vessels based on a disruption of hypoxia (reduced expression of HIF-1α/HIF-2α and cancer stem cell markers) and pericyte/endothelial cell architecture. Interestingly, DAS also abrogated systemic frequencies of the MDSC/Treg cell immunosuppressor cell populations. Combination VAC + DAS therapy provided superior anti-tumor protection versus either monotherapy, which correlated with the enhanced trafficking of antigen-specific CD8+ T effectors into tumor lesions. Overall, these results support the clinical translation of this combination immunotherapy for the treatment of melanoma.
- Copyright © 2013 by The American Association of Immunologists, Inc.