CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness.
CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness.
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DOI：
10.1002/path.5361
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发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Ikeda H
中科院分区：
文献类型：
--
作者：
Inaguma S;Lasota J;Czapiewski P;Langfort R;Rys J;Szpor J;Waloszczyk P;Okoń K;Biernat W;Schrump DS;Hassan R;Kasai K;Miettinen M;Ikeda H
胸膜弥漫性恶性间皮瘤（MPM）是一种高度侵袭性的肿瘤，通常与生存期短有关。CD 70和CD 27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，CD 70和CD 27之间的紧密调节的相互作用通过NFκB途径在促进T细胞扩增和分化中发挥共刺激作用。在血液和实体恶性肿瘤中，CD 70表达异常高，与恶性细胞的免疫逃避有关。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）进行了免疫组化评估，以检测CD 70、CD 27、CD 3、CD 4、CD 8、CD 56、PDCD 1（PD-1）和FOXP 3的表达。20%（34/172）的间皮瘤细胞在细胞膜上表达CD 70。在具有表达CD 70的肿瘤细胞的患者队列中，总体存活率显著降低（p <0.01）。含有较高数量的CD 3+（p <0.01）、CD 4+（p <0.01）、CD 8+（p <0.01）或FOXP 3+（p <0.01）肿瘤浸润淋巴细胞（TIL）的MPM患者显示出显著较差的临床结局。作为MPM患者的潜在独立风险因素，多变量考克斯比例风险回归分析显示间皮瘤细胞上的CD 70表达[风险比（HR）2.25; p =0.010]、较高的FOXP 3 + TIL（HR 2.81; p =0.004）和较高的CD 3 + TIL蓄积（HR 6.12; p <0.001）。相反，作为一个潜在的独立有利因素，确定了较高的CD 27 + TIL积累（HR 0.48; p =0.037）。体外实验和免疫缺陷小鼠模型显示，CD 70通过激活MET-ERK轴增强MPM细胞的侵袭力。在同系小鼠模型中的进一步分析证明了CD 70在免疫逃避中的可能作用。总的来说，这些研究结果表明，CD 70-CD 27途径增强了MPM的恶性表型，并减少了这些肿瘤患者的抗肿瘤免疫反应。这些标志物可能是有用的MPM的预后评估以及靶向治疗。
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.
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