CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro.
CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro.
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DOI：
10.18632/oncotarget.8864
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Pogge von Strandmann E
中科院分区：
文献类型：
--
作者：
Hansen HP;Trad A;Dams M;Zigrino P;Moss M;Tator M;Schön G;Grenzi PC;Bachurski D;Aquino B;Dürkop H;Reiners KS;von Bergwelt-Baildon M;Hallek M;Grötzinger J;Engert A;Paes Leme AF;Pogge von Strandmann E
癌症靶向免疫治疗的目标是破坏微环境中的恶性细胞和肿瘤支持细胞，但保留未受影响的组织。经典型霍奇金淋巴瘤（cHL）的恶性细胞选择性表达CD 30。它们在细胞外囊泡（EV）上释放这种受体，用于与CD 30配体（CD 30 L）阳性旁观者细胞进行肿瘤支持通信。在此，我们研究了CD 30阳性EV如何影响CD 30抗体药物偶联物（ADC）维布妥昔单抗（SGN-35）的疗效。恶性细胞和EV表达活性脱落酶ADAM 10。ADAM 10切割并释放CD 30胞外域（sCD 30），导致EV上SGN-35结合位点逐渐耗尽，并产生ADC治疗的可溶性竞争物。在3D半实体肿瘤微环境模型中，EV保留在基质中，而sCD 30容易渗透到周围的培养基中。这导致与非包埋培养物相比，周围培养基中EV相关CD 30（CD 30 EV）与sCD 30的比率降低。在cHL患者的血浆中也检测到低百分比的CD 30 EV，支持该模型的临床相关性。CD 30 EV而非sCD 30与CD 30 −/CD 30 L+肥大细胞和嗜酸性粒细胞的粘附允许SGN-35的间接结合。此外，SGN-35破坏CD 30阴性细胞，只要它们负载有CD 30 + EV。
The goal of targeted immunotherapy in cancer is to damage both malignant and tumor-supporting cells of the microenvironment but spare unaffected tissue. The malignant cells in classical Hodgkin lymphoma (cHL) selectively express CD30. They release this receptor on extracellular vesicles (EVs) for the tumor-supporting communication with CD30 ligand (CD30L)-positive bystander cells. Here, we investigated how CD30-positive EVs influence the efficacy of the CD30 antibody drug conjugate (ADC) Brentuximab Vedotin (SGN-35). The malignant cells and the EVs expressed the active sheddase ADAM10. ADAM10 cleaved and released the CD30 ectodomain (sCD30), causing a gradual depletion of SGN-35 binding sites on EVs and creating a soluble competitor of the ADC therapy. In a 3D semi-solid tumor microenvironment model, the EVs were retained in the matrix whereas sCD30 penetrated readily into the surrounding culture medium. This resulted in a lowered ratio of EV-associated CD30 (CD30EV) to sCD30 in the surrounding medium in comparison to non-embedded cultures. A low percentage of CD30EV was also detected in the plasma of cHL patients, supporting the clinical relevance of the model. The adherence of CD30EV but not sCD30 to CD30−/CD30L+ mast cells and eosinophils allowed the indirect binding of SGN-35. Moreover, SGN-35 damaged CD30-negative cells, provided they were loaded with CD30+ EVs.
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影响因子：
7.3
作者：
Hansen, Hinrich P.;Engels, Hanna-Mareike;von Strandmann, Elke Pogge
通讯作者：
von Strandmann, Elke Pogge
影响因子：
2.2
作者：
Lamparski, HG;Metha-Damani, A;Le Pecq, JB
通讯作者：
Le Pecq, JB
影响因子：
6
作者：
Horie, R;Gattei, V;Watanabe, T
通讯作者：
Watanabe, T
影响因子：
11.2
作者：
Eichenauer, Dennis A.;Simhadri, Vijaya Lakshmi;Hansen, Hinrich P.
通讯作者：
Hansen, Hinrich P.
影响因子：
3.1
作者：
Andersen, Maja D.;Kamper, Peter;d'Amore, Francesco
通讯作者：
d'Amore, Francesco