Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Mod Pathol. 2019 Sep;32(9):1344-1358. doi: 10.1038/s41379-019-0269-x. Epub 2019 Apr 17.
Amplifications of JAK2, PD-L1, and PD-L2 at 9p24.1 lead to constitutive expression of PD-L1. This, coupled with JAK2-activation dependent upregulation of PD-L1 and adaptive/induced expression leads to higher tumor PD-L1 expression and immune evasion. Renal tumors were therefore evaluated for 9p24.1 amplifications. A combination of next generation sequencing-based copy number analysis, fluorescence in situ hybridization for JAK2/INSL6 and PD-L1/PD-L2 and immunohistochemistry for phospho-STAT3 (downstream target of JAK2), PD-L1, PD-L2, and PD-1 was performed. In this study we interrogated a "Discovery" cohort of 593 renal tumors, a "Validation" cohort of 398 high-grade renal tumors, The Cancer Genome Atlas (879 cases) and other public datasets (846 cases). 9p24.1 amplifications were significantly enriched in renal tumors with sarcomatoid transformation (5.95%, 15/252) when compared to all histologic subtypes in the combined "Discovery", "Validation" and public datasets (16/2636, 0.6%, p < 0.00001). Specifically, 9p24.1 amplifications amongst sarcomatoid tumors in public datasets, the "Discovery" and "Validation" cohorts were 7.7% (6/92), 15.1% (5/33), and 3.1% (4/127), respectively. Herein, we describe 13 cases and amplification status for these was characterized using next generation sequencing (n = 9) and/or fluorescence in situ hybridization (n = 10). Correlation with PD-L1 immunohistochemistry (n = 10) revealed constitutive expression (mean H-score: 222/300, n = 10). Analysis of outcomes based on PD-L1 expression in tumor cells performed on 282 cases ("Validation" cohort) did not reveal a significant prognostic effect and was likely reflective of advanced disease. A high incidence of constitutive PD-L1 expression in tumor cells in the "Validation" cohort (H-Score ≥250/300) was noted amongst 83 rhabdoid (6%) and 127 sarcomatoid renal tumors (7.1%). This suggests additional mechanisms of constitutive expression other than amplification events. Importantly, two patients with 9p24.1-amplified sarcomatoid renal tumors showed significant response to immunotherapy. In summary, a subset of renal tumors with sarcomatoid transformation exhibits constitutive PD-L1 overexpression and these patients should be evaluated for enhanced response to immunotherapy.
9p24.1 处 JAK2、PD-L1 和 PD-L2 的扩增导致 PD-L1 的组成性表达。这与 JAK2 激活依赖性 PD-L1 的上调以及适应性/诱导性表达相结合,导致肿瘤 PD-L1 表达和免疫逃逸更高。因此,对肾肿瘤进行了 9p24.1 扩增评估。进行了下一代测序的基于拷贝数分析、JAK2/INSL6 和 PD-L1/PD-L2 的荧光原位杂交以及磷酸化 STAT3(JAK2 的下游靶标)、PD-L1、PD-L2 和 PD-1 的免疫组化的组合。在这项研究中,我们研究了一个“发现”队列中的 593 例肾肿瘤、一个“验证”队列中的 398 例高级别肾肿瘤、癌症基因组图谱(879 例)和其他公共数据集(846 例)。与联合“发现”、“验证”和公共数据集的所有组织学亚型相比,具有肉瘤样转化的肾肿瘤中 9p24.1 扩增明显丰富(5.95%,15/252)(p<0.00001)。具体而言,在公共数据集、“发现”和“验证”队列中,肉瘤样肿瘤中的 9p24.1 扩增分别为 7.7%(6/92)、15.1%(5/33)和 3.1%(4/127)。在此,我们描述了 13 例病例,并使用下一代测序(n=9)和/或荧光原位杂交(n=10)对这些病例的扩增状态进行了表征。与肿瘤细胞中 PD-L1 免疫组化的相关性(n=10)显示出组成性表达(平均 H 评分:222/300,n=10)。对 282 例病例(“验证”队列)进行的基于肿瘤细胞中 PD-L1 表达的生存分析没有显示出显著的预后效果,这可能反映了晚期疾病。在“验证”队列中,在肿瘤细胞中观察到 PD-L1 的高发生率(H 评分≥250/300)(83 例横纹肌样(6%)和 127 例肉瘤样肾肿瘤(7.1%)。这表明除了扩增事件之外,还有其他导致组成性表达的机制。重要的是,两名 9p24.1 扩增的肉瘤样肾肿瘤患者对免疫治疗有明显反应。总之,具有肉瘤样转化的肾肿瘤亚群表现出组成性 PD-L1 过表达,这些患者应评估对免疫治疗的增强反应。