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Molecular targets for therapy

Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma

Leukemia volume 32, pages 176–183 (2018)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from the National Cancer Institute (R01 CA163881, CA200539, CA211073 and CA214811), the Leukemia and Lymphoma Society (6469-15) and the Multiple Myeloma Research Foundation (to QY); and the National Natural Science Foundation of China (81372536 to SW, 81372545 to CZ). We thank Cassandra Talerico, PhD, Department of Cancer Biology, Cleveland Clinic, for helpful editorial suggestions. This work used the PerkinElmer IVIS Spectrum CT In Vivo Imager that was purchased with funding from National Institutes of Health SIG grant 1S10OD018205-01A1.

Author contributions

QY, QW and SW initiated the work; SW, QW and QY wrote the manuscript; QW, YL, RL and YJ performed majority of the experiments; YZ, JQ and EB performed some experiments; JH and CZ provided critical suggestions to this study.

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Author notes

  1. Q Wang, Y Lu and R Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China

    Q Wang, Y Jiang, S Wang & Q Yi

  2. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Q Wang, Y Lu, R Li, Y Zheng, J Qian, E Bi & Q Yi

  3. Department of Hematology, The MM and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China

    R Li & J Hou

  4. Department of Hematology, and State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, West China Hospital, Chengdu, China,

    Y Zheng

  5. Department of Hematology, Second Hospital of Shandong University, Jinan, China

    C Zheng

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Correspondence to S Wang or Q Yi.

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Wang, Q., Lu, Y., Li, R. et al. Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. Leukemia 32, 176–183 (2018). https://doi.org/10.1038/leu.2017.193

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