Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Cell. 2018 Nov 1;175(4):984-997.e24. doi: 10.1016/j.cell.2018.09.006.
Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.
免疫检查点抑制剂（ICIs）在一些黑色素瘤患者中产生持久的反应，但许多患者没有临床获益，而且这种耐药性的分子基础仍然难以捉摸。在这里，我们利用来自 33 个黑色素瘤肿瘤的单细胞 RNA 测序（scRNA-seq）和计算分析来探究促进免疫逃逸的恶性细胞状态。我们鉴定了一种由恶性细胞表达的耐药性程序，该程序与 T 细胞排斥和免疫逃逸有关。该程序在免疫治疗之前表达，描绘了原位冷区，并在 112 名黑色素瘤患者的独立队列中预测了对抗 PD-1 治疗的临床反应。CDK4/6 抑制在单个恶性细胞中抑制该程序，诱导衰老，并在与免疫治疗联合使用时减少小鼠模型中的黑色素瘤肿瘤生长。我们的研究提供了 ICI 耐药细胞状态的高分辨率图谱，鉴定了具有临床预测性的特征，并提出了克服免疫治疗耐药性的新治疗策略。
