Bone marrow stromal cell-mediated degradation of CD20 leads to primary rituximab resistance in mantle cell lymphoma
Bone marrow stromal cell-mediated degradation of CD20 leads to primary rituximab resistance in mantle cell lymphoma
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骨髓基质细胞介导的 CD20 降解导致套细胞淋巴瘤原发性利妥昔单抗耐药
DOI：
10.1038/s41375-020-01035-x
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发表时间：
2020
期刊：
影响因子：
11.4
通讯作者：
Furukawa Yusuke
中科院分区：
文献类型：
--
作者：
Kuroda Yoshiaki;Yashima-Abo Akiko;Koyama Daisuke;Kikuchi Jiro;Mori Shigehisa;Ito Shigeki;Furukawa Yusuke
CD 20抗原在B细胞性非霍奇金淋巴瘤（NHL）中稳定、均一的表达，是理想的免疫治疗靶点。事实上，靶向CD 20的单克隆抗体极大地改变了B细胞恶性肿瘤的治疗前景，特别是包括套细胞淋巴瘤（MCL）在内的惰性淋巴瘤[1]。对一流的CD 20抗体利妥昔单抗的耐药性并不常见，但却是一个极其重要的临床问题。虽然已经提出了几种机制[2]，但CD 20表达的丧失无疑是利妥昔单抗耐药的最直接和最常见的原因之一。先前的研究表明表观遗传沉默[3]、CD 20基因突变[4]和吞噬细胞的胞饮作用[5]是CD 20下调的潜在机制。在这里，我们报告了CD 20的自噬降解作为利妥昔单抗耐药的一种新机制。最近，我们遇到了MCL的情况下，其中骨髓（BM）浸润缺陷的CD 20表达在诊断和利妥昔单抗为基础的治疗，而淋巴结（LN）病变强烈表达CD 20，并响应良好，以相同的方案。MCL的其他标志物，如细胞周期蛋白D1和CD 5，在诊断样品的LN和BM细胞中以相等的水平表达（图1a）。这一观察结果与Foran等人先前的报告一致。[6]其中25例B细胞NHL患者中有6例（24%）在利妥昔单抗单药治疗后表现出BM浸润的CD 79 α阳性淋巴瘤细胞中CD 20表达的完全丧失或显著降低，其中大多数为惰性类型。相反，即使在治疗后，这些患者的淋巴结中的CD 20表达也一致较强。同样，在B细胞慢性淋巴细胞白血病（B-CLL）中，BM浸润中的表面CD 20水平低于循环肿瘤细胞[7]。Marquez等人[8]为了研究BM中选择性CD 20下调的机制，我们建立了MCL细胞系HBL-2、Jeko-1和SMCH-16的表达CD 20的亚系[9]，并将它们培养在BMSC系UBE 6 T-7 [10]和StromaNKtert [11]或人扁桃体衍生的滤泡树突细胞系HK [12]的汇合饲养层上，以再现贴壁条件（补充图S1 a）。与BMSC而不是滤泡树突状细胞共培养显著降低了MCL细胞上CD 20的表达（图1 B），并阻碍了利妥昔单抗对MCL细胞的补体依赖性细胞毒性（图1 c）。自噬被假设为BMSC介导的CD 20下调的机制，因为p62，选择性自噬的关键介质[13]，在BM浸润的MCL细胞中比LN病变中染色更弱。
The CD20 antigen is an ideal target of immunotherapy because of its stable and uniform expression among B-cell non-Hodgkin lymphomas (NHL). In fact, monoclonal antibodies targeting CD20 have greatly changed the therapeutic landscape of B-cell malignancies, especially indolent lymphomas including mantle cell lymphoma (MCL)[1]. Resistance to the first-in-class CD20 antibody rituximab is not frequent but is an extremely important clinical issue. Although several mechanisms have been proposed [2], loss of CD20 expression is undoubtedly one of the most straightforward and common causes of rituximab resistance. Previous studies have implicated epigenetic silencing [3], CD20 gene mutations [4], and trogocytosis by phagocytes [5] as mechanisms underlying CD20 downregulation. Here, we report autophagic degradation of CD20 as a novel mechanism of rituximab resistance. Recently, we encountered a case of MCL, in which bone marrow (BM) infiltrates were defective for CD20 expression at diagnosis and resistant to rituximab-based treatment, whereas lymph node (LN) lesions expressed CD20 strongly and responded well to the same regimen. Other hallmarks of MCL, such as cyclin D1 and CD5, were expressed at equivalent levels in LN and BM cells of diagnostic samples (Fig. 1 a). This observation is consistent with a previous report by Foran et al.[6], wherein 6 out of 25 patients (24%) with B-cell NHL, mostly indolent types, exhibited the complete loss or tremendous reductions in CD20 expression in BM-infiltrated CD79α-positive lymphoma cells after rituximab monotherapy. In contrast, CD20 expression was uniformly strong in the LNs of these patients even after treatment. Similarly, surface CD20 levels were lower in BM infiltrates than in circulating tumor cells in B-cell chronic lymphocytic leukemia (B-CLL)[7]. Marquez et al.[8] demonstrated that interaction with BM stromal cells (BMSCs) readily decreased the expression of CD20 in BCLL cells in vitro but did not address the mechanisms behind their finding.To investigate the mechanisms of selective CD20 downregulation in the BM, we established luciferaseexpressing sublines of MCL cell lines HBL-2, Jeko-1, and SMCH-16 [9], and cultured them on a confluent feeder layer of BMSC lines UBE6T-7 [10] and StromaNKtert [11] or human tonsil-derived follicular dendritic cell line HK [12] to reproduce adherent conditions (Supplementary Fig. S1a). Coculture with BMSCs, but not follicular dendritic cells, significantly decreased the expression of CD20 on MCL cells (Fig. 1 b) and impeded the complement-dependent cytotoxicity of rituximab toward MCL cells (Fig. 1 c). Autophagy was hypothesized as a mechanism of the BMSC-mediated CD20 downregulation, because p62, a pivotal mediator of selective autophagy [13], was stained more weakly in BM-infiltrated MCL cells than in LN lesions in
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滤泡树突状细胞表达的 Notch 配体可保护生发中心 B 细胞免于凋亡
DOI：
10.4049/jimmunol.0803183
发表时间：
2009
期刊：
The Journal of Immunology
影响因子：
--
作者：
Sun;Xin Zhang;P. Berner;B. Blom;Y. Choi
通讯作者：
Y. Choi
影响因子：
32.4
作者：
Koushik Roy;S. Mitchell;Yi Liu;S. Ohta;Yu;M. Metzig;S. Nutt;A. Hoffmann
通讯作者：
A. Hoffmann
影响因子：
6.5
作者：
Foran, JM;Norton, AJ;Lister, TA
通讯作者：
Lister, TA
影响因子：
6.5
作者：
Marquez, Maria-Elena;Hernandez-Uzcategui, Octavio;Da Costa, Osiris
通讯作者：
Da Costa, Osiris