CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth

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. 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 cell 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.