Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy.
Department of Pathology and Medical Biology, University Medical Center Groningen (UMcG), the Netherlands.
Haematologica. 2019 Mar;104(3):564-575. doi: 10.3324/haematol.2018.196725. Epub 2018 Oct 11.
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.
经典霍奇金淋巴瘤肿瘤细胞表达功能性 CCR5 受体，肿瘤组织表达高水平的 CCL5，提示 CCL5-CCR5 信号参与肿瘤微环境的形成和肿瘤生长。我们使用 CCR5 拮抗剂马拉维若和中和性抗 CCL5 抗体发现，经典霍奇金淋巴瘤细胞分泌的 CCL5 招募间质基质细胞和单核细胞。肿瘤细胞条件培养基对间质基质细胞的“教育”增强了间质基质细胞的增殖和 CCL5 的分泌。反过来，经“教育”的间质基质细胞条件培养基增加了肿瘤细胞的集落形成和单核细胞的迁移，但这些作用被马拉维若所降低。肿瘤细胞条件培养基对单核细胞的“教育”诱导其生长并将其重新编程为表达 IDO 和 PD-L1 并分泌 IL-10、CCL17 和 TGF-β的免疫抑制性肿瘤相关巨噬细胞。经“教育”的单核细胞条件培养基使植物血球凝集素激活的淋巴细胞的生长速度减缓。马拉维若降低了肿瘤细胞的生长，并与多柔比星和 Brentuximab vedotin 协同作用。三维异质球体检测表明，马拉维若不仅拮抗了肿瘤细胞与间质基质细胞和单核细胞共培养生成的异质球体的形成和活力，还拮抗了其生长。在携带肿瘤细胞异种移植物的小鼠中，马拉维若使肿瘤生长减少了 50%以上，并抑制了单核细胞的积累，而没有体重减轻。最后，在经典霍奇金淋巴瘤人类肿瘤组织中，CCL5 和 CD68 的表达呈正相关，且高水平 CCL5 的患者预后不良。总之，由于目前的挑战是寻找对抗免疫抑制性肿瘤微环境形成的分子或新的、毒性较小的药物组合，因此，重新利用的药物马拉维若可能为经典霍奇金淋巴瘤的治疗提供新的机会。
