Affiliation:
1. Washington University in St. Louis
2. Washington University School of Medicine
3. Glasgow Caledonian University
4. Washington University in St. Louis School of Medicine
5. Washington University
6. University of Texas Southwestern
Abstract
Abstract
Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow (BM) 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. Thus, TAMs have become an emerging target of interest. 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 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 pathway using a blocking IL-10R antibody 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 axis is a novel immunotherapy strategy with monotherapy efficacy and can be further combined with current anti-MM therapy to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.
Publisher
Research Square Platform LLC