Mutations in the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signalling pathway are common in melanoma. The BRAF serine/threonine kinase is a key regulator of this pathway. Approximately 60% of melanoma patients have a gain-of-function BRAFV600E mutation, leading to uncontrolled proliferation. BRAF inhibitors have shown clinical benefit, however, emerging evidence suggests that they diminish responses to subsequent immunotherapy, indicating unknown effects on the immune system Given the relatively high incidence of resistance and treatment-related toxicities, it is important to better understand the mechanisms through which BRAF inhibitors work and how they affect immune cells.
Dendritic cells (DC) are professional antigen presenting cells integral to strong anti-tumour T cell responses. However, the effects of BRAF inhibitors on DC function are not understood. Our work utilises in vitro models and ex vivo murine and human primary DCs to explore the functional effects of BRAF inhibitors on DC function, including surface activation marker expression, cytokine production and T cell stimulation. Our preliminary data show that BRAF inhibitors can enhance ex vivo DC activation in mouse models. In stark contrast, ex vivo treatment of human DCs with BRAF inhibitors impedes DC activation by inhibiting proinflammatory cytokine production and downregulating surface activation markers. These data suggest that BRAF inhibitors hinder human DC activation, which may impair subsequent anti-tumour T cell responses.
Importantly, this work demonstrates the divergent responses of mouse and human primary DCs to BRAF inhibition. This highlights a need to elucidate the mechanisms of immune effects, as this may underlie variability between preclinical and clinical data on BRAF inhibitors. Additionally, this may enhance our understanding of the interactions between BRAF inhibitors and immunotherapy.