CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth.
CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth.
复制标题
Maraviroc的CCR5拮抗作用抑制霍奇金淋巴瘤微环境相互作用和异种移植生长。
DOI：
10.3324/haematol.2018.196725
复制
发表时间：
2019-03
期刊：
影响因子：
10.1
通讯作者：
Aldinucci D
中科院分区：
文献类型：
--
作者：
Casagrande N;Borghese C;Visser L;Mongiat M;Colombatti A;Aldinucci D
典型的霍奇金淋巴瘤肿瘤细胞表达功能性CCR 5受体，肿瘤组织表达高水平的CCL 5，表明CCL 5-CCR 5信号传导参与肿瘤微环境形成和肿瘤生长。使用CCR 5拮抗剂马拉韦罗和中和性抗CCL 5抗体，我们发现经典霍奇金淋巴瘤细胞分泌的CCL 5募集间充质基质细胞和单核细胞。肿瘤细胞条件培养液对间充质基质细胞的“教育”促进了间充质基质细胞的增殖和CCL 5的分泌。反过来，受过教育的间充质基质细胞条件培养基增加了肿瘤细胞的克隆生长和单核细胞迁移，但这些作用被马拉韦罗降低。通过肿瘤细胞条件培养基的单核细胞教育诱导其生长并将其重编程为表达IDO和PD-L1并分泌IL-10、CCL 17和TGF-β的免疫抑制性肿瘤相关巨噬细胞。受教育的单核细胞条件培养基减慢植物血凝素激活的淋巴细胞的生长。马拉韦罗可降低肿瘤细胞生长，并与多柔比星和维布妥昔单抗协同作用。三维异球体试验表明，马拉韦罗可抵消肿瘤细胞与间充质基质细胞和单核细胞共培养产生的异球体的形成和活力。在携带肿瘤细胞异种移植物的小鼠中，maraviroc使肿瘤生长减少了50%以上，并抑制单核细胞积聚，而体重没有减轻。最后，在经典型霍奇金淋巴瘤人肿瘤组织中，CCL 5和CD 68表达呈正相关，CCL 5水平高的患者预后差。总之，由于目前的挑战是找到抵消免疫抑制肿瘤微环境形成的分子或新的毒性较小的药物组合，重新使用的药物马拉韦罗可能代表经典霍奇金淋巴瘤治疗的新机会。
Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in tumor-microenvironment formation and tumor growth. Using the CCR5 antagonist, maraviroc, and a neutralizing anti-CCL5 antibody, we found that CCL5 secreted by classic Hodgkin lymphoma cells recruited mesenchymal stromal cells and monocytes. The “education” of mesenchymal stromal cells by tumor cell-conditioned medium enhanced mesenchymal stromal cells’ proliferation and CCL5 secretion. In turn, educated mesenchymal stromal cell-conditioned medium increased the clonogenic growth of tumor cells and monocyte migration, but these effects were reduced by maraviroc. Monocyte education by tumor cell-conditioned medium induced their growth and reprogrammed them towards immunosuppressive tumor-associated macrophages that expressed IDO and PD-L1 and secreted IL-10, CCL17 and TGF-β. Educated monocyte-conditioned medium slowed the growth of phytohemagglutinin-activated lymphocytes. Maraviroc decreased tumor cell growth and synergized with doxorubicin and brentuximab vedotin. A three-dimensional heterospheroid assay showed that maraviroc counteracted both the formation and viability of heterospheroids generated by co-cultivation of tumor cells with mesenchymal stromal cells and monocytes. In mice bearing tumor cell xenografts, maraviroc reduced tumor growth by more than 50% and inhibited monocyte accumulation, without weight loss. Finally, in classic Hodgkin lymphoma human tumor tissues, CCL5 and CD68 expression correlated positively, and patients with high CCL5 levels had poor prognosis. In conclusion, since the present challenges are to find molecules counteracting the formation of the immunosuppressive tumor microenvironment or new, less toxic drug combinations, the repurposed drug maraviroc may represent a new opportunity for classic Hodgkin lym phoma treatment.