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

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 2; pp. 327 - 338
• Main Authors: Yan, Haimeng, He, Donghua, Qu, Jianwei, Liu, Yang, Xu, Ruyi, Gu, Huiyao, Chen, Jing, Li, Yi, Zhang, Enfan, Zhao, Yi, He, Jingsong, Cai, Zhen
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2023; Springer Nature B.V
• Subjects: Apoptosis; Cancer Research; Chemoresistance; Colony-stimulating factor; Cytokines; Drug resistance; Drug Resistance, Neoplasm; Humans; Immunology; Immunotherapy; Interleukins - metabolism; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - metabolism; Macrophages; Macrophages - metabolism; Medicine; Medicine & Public Health; Multiple myeloma; Multiple Myeloma - metabolism; Oncology; Original; Original Article; Phenotypes; Polarization; Surface markers; Polarization; Interleukin-32; Macrophages; Multiple myeloma; Chemoresistance
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-022-03241-1

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.