Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.

The bone marrow (BM) is the primary site of adult haematopoiesis, where stromal elements (e.g. fibroblasts and mesenchymal stem cells [MSCs]) work in concert to support blood cell development. However, the establishment of an abnormal clone can lead to a blood malignancy, such as acute myeloid leukaemia (AML). Despite our increased understanding of the pathophysiology of the disease, patient survival remains suboptimal, mainly driven by the development of therapy resistance. In this review, we highlight the importance of bone marrow fibroblasts and MSCs in health and acute myeloid leukaemia and their impact on patient prognosis. We discuss how stromal elements reduce the killing effects of therapies via a combination of contactdependent (e.g. integrins) and contact-independent (i.e. secreted factors) mechanisms, accompanied by the establishment of an immunosuppressive microenvironment. Importantly, we underline the challenges of therapeutically targeting the bone marrow stroma to improve acute myeloid leukaemia patient outcomes, due to the inherent heterogeneity of stromal cell populations.

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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.