Department of Cancer Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Leukemia. 2018 Jan;32(1):176-183. doi: 10.1038/leu.2017.193. Epub 2017 Jun 19.
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 MM 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.
我们之前的研究表明，巨噬细胞（MФs），尤其是骨髓瘤相关的巨噬细胞（MAMs），可诱导人类骨髓瘤的耐药性。在这里，我们通过使用集落刺激因子 1 受体（CSF1R）阻断 mAbs 来探索靶向 MФs 的潜力，以治疗骨髓瘤。我们的结果表明，CSF1R 阻断特异性抑制了体外小鼠 M2 MФs 和 MAMs 的分化、增殖和存活，并使 MAMs 向 M1 样 MФs 重极化。CSF1R 阻断单独抑制体内骨髓瘤的生长，部分耗尽 MAMs，将 MAMs 极化为 M1 表型，并诱导肿瘤特异性细胞毒性 CD4 T 细胞反应。同样，在骨髓瘤荷瘤 MM 小鼠中遗传耗竭 MФs 也会减缓体内骨髓瘤的生长。此外，CSF1R 阻断与硼替佐米或美法仑等化疗药物联合使用对已建立的骨髓瘤显示出附加的治疗效果。最后，一种完全人源化的 CSF1R 阻断 mAb 与其鼠源对应物相似，能够抑制人 MФs 的分化、增殖和存活。因此，这项研究首次直接在体内证明了 MΦs 和 MAMs 确实对骨髓瘤的发生和发展很重要。我们的结果还表明，通过 CSF1R 阻断 mAbs 靶向 MAMs 可能是一种有前途的方法，可以使骨髓瘤细胞对化疗重新敏感，并促进患者的抗骨髓瘤免疫反应。
