脑转移
癌症研究
医学
黑色素瘤
MAPK/ERK通路
免疫疗法
肿瘤微环境
MEK抑制剂
免疫系统
FOXP3型
CD8型
T细胞
转移
免疫学
癌症
生物
信号转导
内科学
生物化学
作者
Magali de Sauvage,Consuelo Torrini,Edwin Nieblas‐Bedolla,E. Summers,Emily Sullivan,Britney S. Zhang,Emily Batchelor,Braxton Marion,Erika Yamazawa,Samuel C. Markson,Hiroaki Wakimoto,Naema Nayyar,Priscilla K. Brastianos
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2023-12-22
卷期号:26 (5): 889-901
被引量:1
标识
DOI:10.1093/neuonc/noad248
摘要
Abstract 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 signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic inhibition of extracellular signal-regulated kinase (ERK) can improve the efficacy of ICI for BM. Methods We used immunotypical mouse models of BM bearing dual extracranial/intracranial tumors to evaluate the efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-programmed death receptor 1 (PD-1) antibody. We verified target inhibition and drug delivery, then investigated treatment effects on 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 2 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 the limited BBB permeability of LY321, combined LY321 and anti-PD-1 treatment can improve intracranial disease control by amplifying extracranial immune responses, 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.
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