Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Clin Cancer Res. 2019 Nov 1;25(21):6511-6523. doi: 10.1158/1078-0432.CCR-19-0475. Epub 2019 Aug 2.
PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti-PD-1 therapy remains unclear. Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort ( = 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti-PD-1 antibody. Copy-number variations (CNVs) for the genes , and were assayed using a TaqMan copy-number assay in a validation cohort ( = 85). The effect of CDK4/6 inhibitors combined with anti-PD-1 antibody monotherapy was evaluated in PD-1-humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models.
WES revealed several significant gene copy-number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor . The association between gain and innate resistance to anti-PD-1 therapy was validated in 85 patients with melanoma ( < 0.05). RNA-Seq analysis of -normal cell lines and -normal tumors showed altered transcriptional output in TNFα signaling via NF-κB, inflammatory response, and IFNγ response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy ( < 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model.
In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti-PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti-PD-1 antibody for the treatment of advanced melanomas.
PD-1 检查点阻断免疫疗法可诱导晚期黑色素瘤患者产生长期和持久的反应。然而，只有一部分黑色素瘤患者从中受益。触发抗 PD-1 治疗固有耐药的机制尚不清楚。对接受抗 PD-1 抗体治疗的晚期黑色素瘤患者的基线肿瘤活检进行了全外显子组测序（WES）和 RNA 测序（RNA-Seq）分析（训练队列，=31 例）。使用 TaqMan 拷贝数测定法在验证队列（=85 例）中检测基因和的拷贝数变化（CNVs）。评估 CDK4/6 抑制剂联合抗 PD-1 抗体单药治疗在 PD-1 人源化小鼠（C57BL/6-hPD-1）和人源化免疫系统（HIS）患者来源异种移植（PDX）模型中的效果。
WES 揭示了无临床获益队列患者中多个显著的基因拷贝数增益，如 12q14.1 位点，该位点含有。在 85 例黑色素瘤患者中验证了增益与抗 PD-1 治疗固有耐药的相关性（<0.05）。-正常细胞系和 -正常肿瘤的 RNA-Seq 分析显示，TNFα 信号转导途径中的 NF-κB、炎症反应和 IFNγ 反应基因集的转录输出发生改变。此外，CDK4/6 抑制剂（帕博西尼）治疗可增加 PD-L1 蛋白水平，并增强 C57BL/6-hPD-1 黑色素瘤细胞和 HIS PDX 模型的疗效（<0.05）。
总之，我们发现 CDK4 通路的遗传异常与晚期黑色素瘤患者对抗 PD-1 治疗的固有耐药有关。此外，我们的研究为联合 CDK4/6 抑制剂和抗 PD-1 抗体治疗晚期黑色素瘤提供了强有力的依据。
