Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs) induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4+ T cell response. Similarly, genetically depleting MФs in myeloma-bearing MMDTR mice retarded myeloma growth in vivo. Furthermore, the combination of CSF1R blockade and chemotherapy such as bortezomib or melphalan displayed an additive therapeutic efficacy against established myeloma. Finally, a fully human CSF1R blocking mAb, similar to its murine counterpart, was able to inhibit the differentiation, proliferation and survival of human MФs. Thus, this study provides the first direct in vivo evidence that MΦs and MAMs are indeed important for myeloma development and progression. Our results also suggest that targeting MAMs by CSF1R blocking mAbs may be promising methods to (re)sensitize myeloma cells to chemotherapy and promote anti-myeloma immune responses in patients.
Tolerogenic dendritic cells (tDCs) potently induce and maintain tolerance based on their distinct characteristics compared with conventional DCs. Recent reports show that donor or host tDCs promote allograft survival in mice. In this study, the efficacy of third-party tDCs in the prevention of acute graft-versus-host disease (aGVHD) was evaluated. In vitro, tDCs derived from the bone marrow (BM) of D1 mice were induced by GM-CSF, IL-10 and TGF-b1. The phenotypes, expression of cytokines and suppression of tDCs were analysed. In vivo, the effects of adoptive transfer of third-party-tDCs were evaluated in an MHC-mismatched aGVHD mouse model. Survival, body weight, GVHD scoring, histopathological specimens and serum cytokines were analysed in tDCtreated mice and untreated controls. Tolerogenic DCs had low expression of MHC and co-stimulatory molecules, expressed high levels of 'immunosuppressive' cytokines and suppressed allo-CD4 + T cell proliferation. In the B6?D2 mouse model, all aGVHD mice died within 18 days. Fortunately, third-party tDCs transferred at low doses (10 4 ) effectively prolonged survival after allo-BMT. Furthermore, in the mice treated with 10 4 tDCs, serum levels of IL-10/TGF-b were significantly higher and the percentage of Foxp3 + cells continually increased compared with the mice treated with other doses of tDCs. Third-party tDCs play a crucial role in reducing the severity of aGVHD by modulating the secretion of various cytokines and expanding Foxp3 + regulatory T cells, which suggests the possibility of using third-party tDCs for therapeutic applications. Furthermore, special attention should be paid to the optimal range of tDCs for preventing allograft rejection.
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