Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co-stimulatory role in promoting T-cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well-characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD-1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70-expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3+ (p < 0.01), CD4+ (p < 0.01), CD8+ (p < 0.01), or FOXP3+ (p < 0.01) tumour-infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3+ TILs (HR 2.81; p = 0.004), and higher CD3+ TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27+ TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET-ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70-CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti-tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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CD70 表达通过免疫逃避和增强侵袭性与恶性胸膜间皮瘤患者的较差预后相关。

胸膜弥漫性恶性间皮瘤 (MPM) 是一种高度侵袭性的肿瘤，通常与短生存期相关。CD70 和 CD27 分别属于肿瘤坏死因子 (TNF) 和 TNF 受体 (TNFR) 超家族。在生理条件下，CD70 和 CD27 之间紧密调控的相互作用通过 NFκB 通路在促进 T 细胞扩增和分化中发挥共刺激作用。血液和实体恶性肿瘤中异常高的 CD70 表达与恶性细胞中的免疫逃避有关。在这项研究中，对 172 个特征明确的原发性弥漫性 MPM 肿瘤，包括上皮样 (n = 145)、双相 (n = 15) 和肉瘤样 (n = 12) 组织型进行了 CD70、CD27、CD3、CD4、CD8、CD56 的免疫组织化学评估、PDCD1 (PD-1) 和 FOXP3 的表达。20% (34/172) 的间皮瘤细胞在细胞膜上表达 CD70。在肿瘤细胞表达 CD70 的患者队列中，总生存期显着降低（p < 0.01）。含有较多 CD3+ (p < 0.01)、CD4+ (p < 0.01)、CD8+ (p < 0.01) 或 FOXP3+ (p < 0.01) 肿瘤浸润淋巴细胞 (TIL) 的 MPM 患者的临床结果显着更差。作为 MPM 患者潜在的独立危险因素，多变量 Cox 比例风险回归分析显示间皮瘤细胞上的 CD70 表达 [风险比 (HR) 2.25; p = 0.010]、更高的 FOXP3+ TIL（HR 2.81；p = 0.004）和更高的 CD3+ TIL 积累（HR 6.12；p < 0.001）。相比之下，作为一个潜在的独立有利因素，确定了更高的 CD27+ TIL 积累（HR 0.48；p = 0.037）。体外实验和免疫缺陷小鼠模型表明，CD70 通过 MET-ERK 轴激活增强 MPM 细胞的侵袭性。同基因小鼠模型中的进一步分析证明了 CD70 在免疫逃避中的可能作用。总的来说，这些发现表明 CD70-CD27 通路增强了 MPM 的恶性表型并降低了这些肿瘤患者的抗肿瘤免疫反应。这些标志物可能在 MPM 中用于预后评估和靶向治疗。© 2019 大不列颠及爱尔兰病理学会。约翰威利父子公司出版 同基因小鼠模型中的进一步分析证明了 CD70 在免疫逃避中的可能作用。总的来说，这些发现表明 CD70-CD27 通路增强了 MPM 的恶性表型并降低了这些肿瘤患者的抗肿瘤免疫反应。这些标志物可能在 MPM 中用于预后评估和靶向治疗。© 2019 大不列颠及爱尔兰病理学会。约翰威利父子公司出版 同基因小鼠模型中的进一步分析证明了 CD70 在免疫逃避中的可能作用。总的来说，这些发现表明 CD70-CD27 通路增强了 MPM 的恶性表型并降低了这些肿瘤患者的抗肿瘤免疫反应。这些标志物可能在 MPM 中用于预后评估和靶向治疗。© 2019 大不列颠及爱尔兰病理学会。约翰威利父子公司出版