MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells

Abstract

Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocytederived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigenspecific expansion. However, no significant decrease in CD4 þ or CD8 þ T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings.

The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4

“…In this study, we assessed the immunologic effects of dabrafenib and trametinib at clinically relevant exposures on both immune and tumor cells in vitro. The effect on immune cells by dabrafenib was consistent with the literature reports for BRAF inhibitors (10,11). However, we found that the effect of trametinib on immune cells was both complex and context dependent.…”

“…Preclinical and limited clinical findings have suggested that immunomodulatory effects in the tumor microenvironment and on circulating immune cells by a BRAF inhibitor alone and the combination of a BRAF inhibitor with a MEK inhibitor is context-dependent (8,(17)(18)(19)(20). On the other hand, concerns have been raised regarding the potential immunosuppressive activity of MEK inhibitors due to their immunosuppressive activity in vitro (10). However, the studies have been limited in scope and lack in vivo validation in mouse models.…”

“…BRAF inhibitors, such as vemurafenib, have been shown to increase immune response and efficacy in combination with immunomodulators in preclinical models (8,9). However, MEK inhibitors, including trametinib, have been reported to be immunosuppressive in vitro, which has limited the in vivo assessment of MEK inhibitor combinations with immunotherapies (10). In this study, we assessed the immunologic effects of dabrafenib and trametinib at clinically relevant exposures on both immune and tumor cells in vitro.…”

PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor–Treated Melanoma Patients

“…This was particularly important as previous studies have shown that MEK inhibitors are potentially immunosuppressive (40,41). We found no evidence for marked immunosuppressive effects in the TILs in the sequential biopsies taken from patients treated with Combi, which appeared comparable to those in patients treated with BRAFi monotherapy.…”

The kinase inhibitors dabrafenib and trametinib affect isolated immune cell populations

“…5 While our results with dabrafenib were similar to the reported effects of vemurafenib on T lymphocytes, the BRAFi BMS908662, has been shown to enhance T-cell proliferation 6 (and reviewed in). 3 Furthermore, a recent retrospective analysis of peripheral lymphocytes reported that vemurafenib, but not dabrafenib, -treated patients had decreased peripheral lymphocyte counts and altered CD4 C T-lymphocyte phenotype and function, as compared with baseline samples.…”