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Interleukin-32γ promotes macrophage-mediated chemoresistance by inducing CSF1-dependent M2 macrophage polarization in multiple myeloma

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Abstract

Macrophages (MΦs) are an abundant component in the multiple myeloma (MM) environment and contribute to MM drug resistance. We previously showed that interleukin-32 (IL-32) is highly expressed in MM patients and induces the immunosuppressive function of MΦs. The present study was designed to explore the role of IL-32 in MΦ-mediated MM drug resistance and the underlying mechanism. Our analysis revealed that IL-32 expression was upregulated in relapsed MM patients and associated with CD206+ M2 MΦ infiltration. Subsequently, we found that the most active isoform, IL-32γ, promoted MΦs to protect MM cells from drug-induced apoptosis both in vitro and in vivo. Furthermore, by evaluating many parameters, including surface markers, cytokines, metabolic enzymes and characteristic molecules, IL-32γ was verified to induce the polarization of M2 MΦs, a function that was partly dependent on increasing the expression of colony-stimulating factor 1 (CSF1). Taken together, the results of our study indicate that IL-32γ promotes MΦ-mediated MM drug resistance and modifies MΦs toward the M2 phenotype, providing a crucial theoretical basis for targeted MΦ immunotherapy.

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Funding

This work was supported by grants from the National Natural Science Foundation of China [Grant numbers 81900209 and 81872322], Natural Science Foundation of Zhejiang Province [Grant number LQ22H080001] and Zhejiang Key Research and Development Project [Grant number 2020C03014].

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Author notes

  1. Haimeng Yan and Donghua He are contributed equally to this work.

Authors and Affiliations

  1. College of Medicine, Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University, Qingchun Road 79, Hangzhou, China

    Haimeng Yan, Donghua He, Jianwei Qu, Yang Liu, Ruyi Xu, Huiyao Gu, Jing Chen, Yi Li, Enfan Zhang, Yi Zhao, Jingsong He & Zhen Cai

  2. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China

    Zhen Cai

  3. Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, China

    Zhen Cai

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  1. Haimeng Yan
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  2. Donghua He
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  3. Jianwei Qu
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  4. Yang Liu
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  10. Yi Zhao
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Contributions

HY and JQ contributed to conceptualization, formal analysis, validation and writing—original draft. YL and RX contributed to data curation and writing—review and editing. HG, DH and YL contributed to investigation, software and methodology. EZ, YZ and JH contributed to visualization, project administration, and resources, JC and ZC contributed to funding acquisition, supervision, project administration, and validation.

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Correspondence to Zhen Cai.

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Yan, H., He, D., Qu, J. et al. Interleukin-32γ promotes macrophage-mediated chemoresistance by inducing CSF1-dependent M2 macrophage polarization in multiple myeloma. Cancer Immunol Immunother 72, 327–338 (2023). https://doi.org/10.1007/s00262-022-03241-1

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