Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma.

ABSTRACT: Our previous studies showed that macrophages (M?s), especially myeloma-associated M?s (MAMs), induce chemoresistance in human myeloma. Here we explored the potential of targeting M?s, 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 M?s and MAMs, and repolarized MAMs towards M1-like M?s 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 M?s 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 M?s. Thus, this study provides the first direct in vivo evidence that M?s 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.

SUBMITTER: Wang Q 

PROVIDER: S-EPMC5927777 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature