Vemurafenib, a small molecule inhibitor of the BrafV600E mutation present in 60% of patient melanomas, has lead to promising results in the clinic. Unlike broad spectrum MEK pathway inhibitors, which have significant off-target effects, specific inhibition of BrafV600E does not impair host immunity, raising the interesting idea that vemurafenib may in fact enhance the host immune response to Braf-mutation bearing melanomas. To test this hypothesis, we have utilized the Tyr-CreERT BrafCA Ptenlox/lox (Braf/Pten) mice, an inducible model of BrafV600E-mutated melanoma. These mice provide an immune competent system in which to characterize the effects of BrafV600E-inhibition on the host immune response to melanoma. Our work demonstrates that treating Braf/Pten tumor-bearing mice with vemurafenib completely arrests the growth of established tumors, and significantly enhances the proportion of CD8 T cells infiltrating dermal melanomas. BrafV600E-inhibition also significantly decreases the proportion of immunosuppressive Treg cells infiltrating the tumor, resulting in a more favorable ratio of CD8 effectors to Tregs than in untreated tumors. Furthermore, CD8 T cell depletion studies have confirmed that these CD8 T cells provide potent long-term tumor control even after BrafV600E-inhibition is discontinued. This work serves as a proof-of-principle that vemurafenib, and possibly other targeted molecular therapies, can enhance endogenous anti-tumor immunity.
- Copyright © 2013 by The American Association of Immunologists, Inc.