IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

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Publication Details

Journal
Leukemia
Published
2024-08-30
DOI
https://doi.org/10.1038/s41375-024-02391-8
Citations
32
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
13.18

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article

IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma

S. Corradini, Obed Asare, Diane E. Bender, Ola Adebayo et al.
32 citations
Leukemia
Multiple Myeloma Research and Treatments
13.18
article

IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma

S. Corradini, Obed Asare, Diane E. Bender, Ola Adebayo, Mark A. Fiala, Ravi Vij, Monica Shokeen, Jennifer Sun, Mark Williams, Barbara Muz, Yixuan Chen, Katerina Miari, Berit Lubben, Sarah Kelley, Mina Maksimos, Kinan Alhallak, Feda Azab, Abdel Kareem Azab, Shaomeng Wang, Hannah Bash, Chaelee Park, Camila Diedrich, Haibin Zhou
article en
32 citations

Abstract

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

LeukemiaVol. 38(11)
Barnes-Jewish Hospital (US), Glasgow Caledonian University (GB), Washington University in St. Louis (US), University of Michigan (US), Southwestern Medical Center (US), Jewish Hospital (US), The University of Texas Southwestern Medical Center (US)
Cancer Prevention and Research Institute of Texas, Alvin J. Siteman Cancer Center, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 1%
Multiple Myeloma Research and Treatments
13.18
DOIOpen Access PDFOpenAlex
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