A growing body of evidence suggests that BRAF-inhibitors, in addition to their acute tumor growth-inhibitory effects, can also promote immune responses to melanoma. The present studies aimed to define the immunological basis of BRAF-inhibitor therapy using the Braf/Pten model of inducible, autochthonous melanoma on a pure C57BL/6 background. In the tumor microenvironment, PLX4720 functioned by on-target mechanisms to selectively decrease both the proportions and absolute numbers of CD4+Foxp3+ regulatory T cells (Treg) and CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs), while preserving numbers of CD8+ effector T cells. In PLX4720-treated mice, intratumoral Treg populations were quantitatively lost, demonstrating enhanced apopotosis. CD11b+ myeloid cells taken from PLX4720-treated tumors also exhibited decreased immunosuppressive function on a per-cell basis. In accordance with a reversion of tumor immune suppression, tumors that had been treated with PLX4720 grew with reduced kinetics after treatment was discontinued, and this growth delay was dependent on CD8 T cells. These findings demonstrate that BRAF inhibition selectively reverses two major mechanisms of immunosuppression in melanoma, and liberates host adaptive anti-tumor immunity.
- Received April 18, 2014.
- Revision received August 8, 2014.
- Accepted August 14, 2014.
- Copyright © 2014, American Association for Cancer Research.