MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells.
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 monocyte-derived 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 antigen-specific expansion. However, no significant decrease in CD4(+) or CD8(+) 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.
Authors' Affiliations: GlaxoSmithKline Vaccines, Rixensart, Belgium.
Laura J
LJ
Vella
Anupama
A
Pasam
Nektaria
N
Dimopoulos
Miles
M
Andrews
Ashley
A
Knights
Anne-Laure
AL
Puaux
Jamila
J
Louahed
Weisan
W
Chen
Katherine
K
Woods
Jonathan S
JS
Cebon
D000951:Antigens, Neoplasm / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D045142:Cross-Priming / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010091:Oximes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology
D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007093:Imidazoles; D008070:Lipopolysaccharides; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib