Department of Molecular and Translational Medicine, Section of Pathology.
Pathology Unit, ASST Spedali Civili di Brescia.
Am J Surg Pathol. 2021 Oct 1;45(10):1428-1438. doi: 10.1097/PAS.0000000000001747.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm derived from plasmacytoid dendritic cells (pDCs). In this study, we investigated by immunohistochemical analysis the expression of E-cadherin (EC) on pDCs in reactive lymph nodes and tonsils, bone marrow, and in BPDCN. We compared the expression of EC in BPDCN to that in leukemia cutis (LC) and cutaneous lupus erythematosus (CLE), the latter typically featuring pDC activation. In BPDCN, we also assessed the immunomodulatory activity of malignant pDCs through the expression of several type I interferon (IFN-I) signaling effectors and downstream targets, PD-L1/CD274, and determined the extent of tumor infiltration by CD8-expressing T cells. In reactive lymph nodes and tonsils, pDCs expressed EC, whereas no reactivity was observed in bone marrow pDCs. BPDCN showed EC expression in the malignant pDCs in the vast majority of cutaneous (31/33 cases, 94%), nodal, and spleen localizations (3/3 cases, 100%), whereas it was more variable in the bone marrow (5/13, 38,5%), where tumor cells expressed EC similarly to the skin counterpart in 4 cases and differently in other 4. Notably, EC was undetectable in LC (n=30) and in juxta-epidermal pDCs in CLE (n=31). Contrary to CLE showing robust expression of IFN-I-induced proteins MX1 and ISG5 in 20/23 cases (87%), and STAT1 phosphorylation, BPDCN biopsies showed inconsistent levels of these proteins in most cases (85%). Expression of IFN-I-induced genes, IFI27, IFIT1, ISG15, RSAD2, and SIGLEC1, was also significantly (P<0.05) lower in BPDCN as compared with CLE. In BPDCN, a significantly blunted IFN-I response correlated with a poor CD8+T-cell infiltration and the lack of PD-L1/CD274 expression by the tumor cells. This study identifies EC as a novel pDC marker of diagnostic relevance in BPDCN. The results propose a scenario whereby malignant pDCs through EC-driven signaling promote the blunting of IFN-I signaling and, thereby, the establishment of a poorly immunogenic tumor microenvironment.
原始滤泡树突状细胞肉瘤（BPDCN）是一种来源于浆细胞样树突状细胞（pDC）的侵袭性肿瘤。在这项研究中，我们通过免疫组化分析，研究了反应性淋巴结和扁桃体、骨髓中的 pDC 以及 BPDCN 中 E-钙黏蛋白（EC）的表达。我们将 BPDCN 中的 EC 表达与白血病皮肤浸润（LC）和皮肤红斑狼疮（CLE）进行了比较，后者通常以 pDC 激活为特征。在 BPDCN 中，我们还通过表达几种 I 型干扰素（IFN-I）信号效应子和下游靶标 PD-L1/CD274 评估了恶性 pDC 的免疫调节活性，并确定了 CD8 表达 T 细胞浸润肿瘤的程度。在反应性淋巴结和扁桃体中，pDC 表达 EC，而骨髓中的 pDC 则无反应。BPDCN 在绝大多数皮肤（33/33 例，94%）、淋巴结和脾脏病变（3/3 例，100%）中恶性 pDC 中表达 EC，而骨髓中的表达则更为多变（5/13，38.5%），其中 4 例肿瘤细胞与皮肤对应物相似地表达 EC，而另外 4 例则不同。值得注意的是，LC（n=30）和 CLE 表皮下 pDC（n=31）中均未检测到 EC。与 CLE 中 20/23 例（87%）强烈表达 IFN-I 诱导的蛋白 MX1 和 ISG5 以及 STAT1 磷酸化相反，BPDCN 活检在大多数情况下显示这些蛋白的表达水平不一致（85%）。IFN-I 诱导基因 IFI27、IFIT1、ISG15、RSAD2 和 SIGLEC1 的表达在 BPDCN 中也明显（P<0.05）低于 CLE。在 BPDCN 中，IFN-I 反应明显减弱与 CD8+T 细胞浸润不良以及肿瘤细胞缺乏 PD-L1/CD274 表达相关。本研究确定 EC 是 BPDCN 中具有诊断相关性的新型 pDC 标志物。结果表明，恶性 pDC 通过 EC 驱动的信号传导促进 IFN-I 信号的减弱，从而建立一个免疫原性差的肿瘤微环境。
