Immune Responses to BRAF-Targeted Therapy in Melanoma: Is Targeted Therapy Immunotherapy?

Therapies targeting the mitogen-activated protein kinase signaling pathway can induce profound tumor regression in patients with advanced BRAF-mutated melanoma. Most patients develop resistance after several months of treatment, which is typically followed by rapid disease progression and death. BRAF- and mitogen-activated protein kinase kinase (MEK)-targeted therapies were initially thought to exert their therapeutic effects through direct inhibition of signaling within the tumor cell, resulting in cell death. Recent evidence suggests that BRAF-targeted therapy also augments the host immune response to melanoma. This is characterized by enhanced expression of melanoma differentiation antigens, reduced levels of immunosuppressive cytokines in the micro environment, and a CD8 T-cell response and T-cell-mediated cytotoxicity. These changes are noted within days of starting therapy, correlate with tumor response, reverse with resistance, and occur in metastatic and advanced, operable disease. Enhanced PDL-1 expression by melanoma cells and increased markers of immune exhaustion, including PD-1 and TIM-1, have been identified, suggesting that the immune response is down-modulated before resistance occurs. These findings indicate that BRAF- and MEK-targeted therapies have multiple, complex, and interrelated mechanisms of action and validate the investigation of combination treatment strategies with targeted therapy and immune checkpoint inhibitors, as well as other therapies that modulate the immune microenvironment. They also lend support for clinical trials investigating preoperative and adjuvant BRAF-targeted therapy for high-risk, BRAF-mutated melanoma. Together, these studies will enhance our understanding of the mechanism of action of BRAF-targeted therapies and may identify additional opportunities to improve the outcome of patients with advanced melanoma.