The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.
The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.
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ERK 抑制剂 LY3214996 可增强 BRAFV600E 黑色素瘤脑转移临床前小鼠模型中的抗 PD-1 免疫治疗。
DOI：
10.1093/neuonc/noad248
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发表时间：
2024
期刊：
影响因子：
15.9
通讯作者：
Brastianos,PriscillaK
中科院分区：
文献类型：
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作者：
deSauvage,MagaliA;Torrini,Consuelo;Nieblas-Bedolla,Edwin;Summers,ElizabethJ;Sullivan,Emily;Zhang,BritneyS;Batchelor,Emily;Marion,Braxton;Yamazawa,Erika;Markson,SamuelC;Wakimoto,Hiroaki;Nayyar,Naema;Brastianos,PriscillaK
免疫检查点抑制剂（ICI）已经彻底改变了癌症治疗；然而，只有一部分脑转移（BM）患者对ICI有反应。有丝分裂原激活的蛋白激酶信号通路的激活突变在BM中是常见的。本研究的目的是评估细胞外信号调节激酶（ERK）的治疗性抑制是否可以提高ICI治疗BM的疗效。方法采用双颅外/颅内肿瘤BM小鼠模型，评价选择性ERK抑制剂LY3214996 （LY321）和抗程序性死亡受体1 （PD-1）抗体单药和双药治疗的疗效。我们验证了靶点抑制和药物递送，然后使用高参数流式细胞术、多重免疫测定和t细胞受体谱分析研究了治疗对t细胞反应和肿瘤免疫微环境的影响。结果我们发现LY321和抗pd -1双重治疗显著提高了2种brafv600e突变小鼠黑色素瘤模型的总生存率，但在kras突变小鼠肺腺癌模型中没有改善。我们证明，尽管LY321具有有限的血脑屏障（BBB）渗透性，但LY321和抗pd -1联合治疗增加了肿瘤浸润的CD8+效应T细胞，拓宽了颅外肿瘤中的T细胞受体库，丰富了外周和脑共享的T细胞克隆，并减少了肿瘤中的免疫抑制细胞因子和细胞群。结论尽管LY321的血脑屏障通透性有限，但LY321联合抗pd -1治疗可通过增强颅外免疫反应来改善颅内疾病的控制，突出了颅外肿瘤在驱动颅内治疗反应中的作用。联合ERK和PD-1抑制是一种很有前景的治疗方法，值得进一步研究黑色素瘤BM患者。
BackgroundImmune 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.MethodsWe 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.ResultsWe 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.ConclusionsDespite 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.