BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (~6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltrate and a decrease in immunosuppressive cytokines. However, there is also increased expression of the immunomodulatory molecule PD-L1, which may contribute to resistance. Based on these findings, we hypothesized that BRAF-targeted therapy may synergize with PD-1 pathway blockade to enhance anti-tumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten-/- syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in intratumoral CD8+ T cell density and cytokine production, similar to effects of BRAF inhibition in patients. In this model CD8+ T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD-1 or anti-PD-L1 blockade together with BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions remain. Further studies using this new melanoma model may provide therapeutic insights, including optimal timing and sequence of therapy.
- Received December 4, 2013.
- Revision received April 4, 2014.
- Accepted April 21, 2014.
- Copyright © 2014, American Association for Cancer Research.