Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Mod Pathol. 2018 Jul;31(7):1155-1163. doi: 10.1038/s41379-018-0034-6. Epub 2018 Feb 15.
Inflammatory myofibroblastic tumor is a rare mesenchymal tumor occurring at many anatomic sites, with a predilection for children and young adults. Often indolent, they can be locally aggressive and can metastasize, resulting in significant morbidity and mortality. Therapeutic options are often limited. The identification of underlying kinase mutations has allowed the use of targeted therapy in a subset of patients. Unfortunately, not all tumors harbor mutations and resistance to tyrosine kinase inhibitor therapy is a potential problem. We hypothesized that these tumors may be amenable to PD-L1 therapy given the immune nature of the tumor. PD-L1 expression in inflammatory myofibroblastic tumors has not yet been defined. The purpose of this study was to explore PD-L1 expression in inflammatory myofibroblastic tumors, as adaptive PD-L1 expression is known to enrich for response to anti-PD-1/PD-L1 therapies. Expression of PD-L1 (clone SP142) was assessed in 35 specimens from 28 patients. Positivity was defined as membranous expression in ≥5% of cells and evaluated separately in tumor and immune cells. Adaptive vs. constitutive patterns of tumor cell PD-L1 expression were assessed. PD-L1 status was correlated with clinicopathologic features. CD8 T cell infiltrates were quantified by digital image analysis. ALK status was assessed by immunohistochemistry and/or FISH. Twenty-four (69%) tumors had PD-L1(+) tumor cells and 28 (80%) showed PD-L1(+) immune cells. Most recurrent and metastatic tumors (80%) and ALK(-) tumors (88%) were PD-L1(+). Adaptive PD-L1 expression was present in 23 (96%) of PD-L1(+) tumors, which also showed a three-four fold increase in CD8 T cell infiltration relative to PD-L1(-) tumors. Constitutive PD-L1 expression was associated with larger tumor size (p = 0.002). Inflammatory myofibroblastic tumors show frequent constitutive and adaptive PD-L1 expression, the latter of which is thought to be predictive of response to anti-PD-1. These data support further investigation into PD-1/PD-L1 blockade in this tumor type.
炎性肌纤维母细胞瘤是一种罕见的间叶性肿瘤，发生于许多解剖部位，好发于儿童和年轻成人。通常惰性，它们可能具有局部侵袭性，并可能转移，导致显著的发病率和死亡率。治疗选择通常有限。潜在激酶突变的鉴定允许在一部分患者中使用靶向治疗。不幸的是，并非所有肿瘤都存在突变，对酪氨酸激酶抑制剂治疗的耐药性是一个潜在的问题。我们假设，鉴于肿瘤的免疫性质，这些肿瘤可能对 PD-L1 治疗有效。炎性肌纤维母细胞瘤中的 PD-L1 表达尚未确定。本研究的目的是探讨炎性肌纤维母细胞瘤中 PD-L1 的表达，因为适应性 PD-L1 表达已知可增强对抗 PD-1/PD-L1 治疗的反应。评估了来自 28 名患者的 35 个标本中的 PD-L1（克隆 SP142）表达。阳性定义为膜表达≥5%的细胞，并分别在肿瘤细胞和免疫细胞中评估。评估了肿瘤细胞 PD-L1 表达的适应性与组成性模式。PD-L1 状态与临床病理特征相关。通过数字图像分析量化 CD8 T 细胞浸润。通过免疫组化和/或 FISH 评估 ALK 状态。24 例（69%）肿瘤的肿瘤细胞 PD-L1（+），28 例（80%）肿瘤的免疫细胞 PD-L1（+）。大多数复发性和转移性肿瘤（80%）和 ALK（-）肿瘤（88%）为 PD-L1（+）。23 例（96%）PD-L1（+）肿瘤存在适应性 PD-L1 表达，与 PD-L1（-）肿瘤相比，CD8 T 细胞浸润增加了三到四倍。组成性 PD-L1 表达与较大的肿瘤大小相关（p=0.002）。炎性肌纤维母细胞瘤显示频繁的组成性和适应性 PD-L1 表达，后者被认为是对抗 PD-1 反应的预测指标。这些数据支持进一步研究该肿瘤类型的 PD-1/PD-L1 阻断。
