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BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic ERK inhibition can improve the efficacy of ICI for BM.METHODS: We used immunotypical mouse models of brain metastasis bearing dual extracranial/intracranial tumors to evaluate efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-PD-1 antibody. We verified target inhibition and drug delivery and investigated treatment-induced changes in T cell response and tumor-immune microenvironment using high-parameter flow cytometry, multiplex immunoassays and T cell receptor profiling.RESULTS: We found that dual treatment with LY321 and anti-PD-1 significantly improved overall survival in two BRAFV600E-mutant murine melanoma models but not in KRAS-mutant murine lung adenocarcinoma. We demonstrate that although LY321 has limited blood brain barrier (BBB) permeability, combined LY321 and anti-PD-1 therapy increases tumor-infiltrating CD8+ effector T cells, broadens the T cell receptor repertoire in the extracranial tumor, enriches T cell clones shared by the periphery and brain, and reduces immunosuppressive cytokines and cell populations in tumors.CONCLUSIONS: Despite limited BBB permeability of LY321, combination LY321 and anti-PD-1 treatment amplifies extracranial immune responses that improve intracranial disease control, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.