Background: Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. Methods: We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. Results: Immunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion of CDKN2A was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by CDK4/6 inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a(-/-) AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 or CDK4/6 inhibitor alone. Conclusions: We identified a novel therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in the more than 40% of patients with MPM who demonstrate loss of CDKN2A.

中文翻译：

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抑制CDK4 / 6克服了对恶性间皮瘤PD-1阻滞的主要抵抗力。

背景：尽管目前有大量PD-1阻滞治疗的恶性胸膜间皮瘤（MPM）患者，但仍未实现对治疗对检查点免疫疗法耐药的合理治疗策略的基础的见解。我们的目标是开发一种新颖的治疗方法，以克服MPM对PD-1阻断的主要耐药性。方法：我们在接受nivolumab治疗的MPM患者（4位反应者和4位非反应者）中产生了对PD-1阻断抗性的转录组特征。我们使用TCGA MPM队列（N = 73）来确定哪些基因组改变与抗药性相关。我们测试了已鉴定分子的调节是否可以克服具有免疫功能的小鼠恶性间皮瘤模型中对PD-1阻滞的抗性。结果：通过将我们的抗PD-1抗性标记应用于TCGA队列进行的免疫基因组学分析表明，CDKN2A的缺失与对PD-1阻断的主要抗性高度相关。在CDK4 / 6抑制可以克服对PD-1阻断的抵抗的假设下，我们测试了CDK4 / 6抑制剂是否可以克服源自Cdkn2a（-/-）AB1恶性间皮瘤细胞的皮下肿瘤对PD-1阻断的抵抗，对PD-1封锁有抵抗力。与单独使用抗PD-1或CDK4 / 6抑制剂相比，每日口服CDK4 / 6抑制剂（abemaciclib或palbociclib）和腹膜内抗PD-1治疗的组合显着抑制了肿瘤的生长。结论：我们确定了一种新的治疗靶标CDK4 / 6，可通过全面的免疫基因组学方法克服对PD-1阻断的主要耐药性。