CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis.
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis.
复制标题
在脑转移的临床前模型中，CDK4/6 抑制使颅内肿瘤对 PD-1 阻断敏感。
DOI：
10.1158/1078-0432.ccr-23-0433
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Brastianos,Priscil
中科院分区：
文献类型：
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作者：
Nayyar,Naema;deSauvage,MagaliA;Chuprin,Jane;Sullivan,EmilyM;Singh,Mohini;Torrini,Consuelo;Zhang,BritneyS;Bandyopadhyay,Sushobhana;Daniels,KeithA;Alvarez-Breckenridge,Christopher;Dahal,Ashish;Brehm,MichaelA;Brastianos,Priscil
目的脑转移瘤发病率高，且对免疫检查点抑制剂耐药。我们评估了CDK 4/6抑制剂（CDKi）abemaciclib是否可以在黑色素瘤和乳腺癌脑转移的小鼠模型中使颅内肿瘤对程序性细胞死亡蛋白1（PD-1）抑制敏感。使用免疫荧光、多重免疫测定、高参数流式细胞术和T细胞受体分析评价了对颅内和颅外肿瘤免疫微环境（TIME）的治疗效果。使用流式细胞术对具有人源化免疫系统的小鼠进行评估，以研究CDKi对人类T细胞发育的影响。ResultsWe发现，abemaciclib与PD-1抑制剂联合使用可降低小鼠的肿瘤负荷，提高总体生存率。时间，这是不同的肿瘤的解剖位置的基础上，改变与CDKi和PD-1抑制在器官特异性的方式。abemaciclib和抗PD-1联合治疗增加了颅内肿瘤中CD 8+效应T细胞亚群的募集和扩增，耗尽了CD 4+调节性T（Treg）细胞，并降低了免疫抑制细胞因子的水平。在植入人类免疫系统的免疫缺陷小鼠中，abemaciclib治疗支持CD 8 +T细胞和Treg细胞耗竭的发育和维持。结论我们的结果突出了颅内和颅外肿瘤的不同特性，并支持在脑转移患者中联合抑制CDK 4/6和PD-1的临床研究。参见Margolin的相关评论，第257页
PurposeBrain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis.Experimental DesignTreatment response was evaluatedin vivousing immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor–immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development.ResultsWe found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti–PD-1 treatment increased recruitment and expansion of CD8+effector T-cell subsets, depleted CD4+regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+T cells and depleted Treg cells.ConclusionsOur results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases.See related commentary by Margolin, p. 257