BRAF/MEK inhibition may counteract immunosuppression by BRAF V600 mutations

Various studies have demonstrated that immunosuppressive mechanisms can be reversed by blocking the effects of mutant BRAF. BRAF inhibitors can downregulate IL-6, IL-10, and VEGF; decrease the recruitment of Tregs and MDSCs; increase recruitment of CTLs; and increase MHC-I and antigen expression. However, there does seem to be a potential increase in the checkpoint molecules PD-1 and PD-L1.

Experiments have also demonstrated that inhibition of BRAF V600E can increase immune infiltration of the tumour and can lead to a measurable increase in the presence of cytotoxic T cells, both CD4⁺ and CD8⁺, which are important in different phases of the T-cell response.

When 2 steps in the MAPK signaling are blocked with inhibitors of BRAF combined with inhibitors of MEK, a similar reduction in the immunosuppressive microenvironment of BRAF-mutant melanoma is observed.

Mandalà M, et al. Lab Invest. 2017;97(2):166-175. Copyright © 2016, Springer Nature. Reprinted with permission by Springer Nature.