Mathios Dimitrios, Ruzevick Jacob, Jackson Christopher M, Xu Haiying, Shah Sagar R, Taube Janis M, Burger Peter C, McCarthy Edward F, Quinones-Hinojosa Alfredo, Pardoll Drew M, Lim Michael
Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Neurooncol. 2015 Jan;121(2):251-9. doi: 10.1007/s11060-014-1637-5. Epub 2014 Oct 28.
Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.
脊索瘤是一种罕见的恶性肿瘤，据推测起源于脊索的残余组织。目前，人们对脊索瘤与宿主免疫系统之间的相互作用了解甚少。检查点蛋白PD-1由循环淋巴细胞表达，是激活和耗竭的标志物。其配体PD-L1（B7-H1，CD274）和PD-L2（B7-DC，CD273）在多种人类癌症中表达；然而，此前尚未在脊索瘤中报道过该通路。我们使用流式细胞术和RT-PCR分析了三种已建立的原发性和复发性脊索瘤细胞系（U-CH1、U-CH2和JHC7），并对10例患者的脊索瘤组织进行了免疫组织化学分析，以鉴定和定位PD-1通路蛋白的表达。PD-1配体并非由脊索瘤细胞组成性表达，但在所有检测的细胞系中，它们的表达在促炎细胞因子的作用下被诱导。在石蜡包埋组织中，我们发现3/6例肿瘤浸润淋巴细胞表达PD-1。我们还发现，尽管脊索瘤细胞未表达显著水平的PD-L1，但在肿瘤浸润巨噬细胞和肿瘤浸润淋巴细胞上观察到了PD-L1表达。我们的研究表明，在分析的一部分脊索瘤微环境中存在PD-1、PD-L1和PD-L2。未来需要开展研究来评估PD-1通路对脊索瘤免疫抑制微环境的作用。
