IL-10R Inhibition Reprograms Tumor-Associated Macrophages and Reverses Drug Resistance in Multiple Myeloma

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.