CSF‐1R inhibition disrupts the dialog between leukaemia cells and macrophages and delays leukaemia progression

Abstract

Research in the last few years has revealed that leukaemic cells can remodel the bone marrow niche into a permissive environment favouring leukaemic stem cell expansion. Tumour‐associated macrophages (TAMs) are prominent components of the tumour microenvironment and play an important role in the onset and progression of solid tumours. However, little is known about their role in the development of acute lymphoblastic leukaemia (ALL). Using a unique mouse model of T‐ALL induced by injection of EL4 T‐cell lymphoma cells to syngeneic C57BL/6 mice, we report herein that ALL leads to the invasion of leukaemia‐associated monocyte‐derived cells (LAMs) into the bone marrow and spleen of T‐ALL mice. Furthermore, we found that leukaemia cells could polarize bone marrow–derived macrophages (BMDMs) into LAMs. In turn, LAMs were able to protect leukaemia cells from drug‐induced apoptosis in vitro. Therapies targeted against the TAMs by inhibiting colony stimulating factor‐1 receptor (CSF‐1R) have emerged as a promising approach for cancer treatment. In this study, we demonstrate that CSF‐1R inhibition inhibits the viability of BMDMs, blocks LAMs polarization and reduces the abundance of LAMs in T‐ALL mice. In vivo, combination treatment of CSF‐1R inhibitor and vincristine (VCR) dramatically increased the survival of T‐ALL mice and delayed leukaemia progression compared with VCR monotherapy. Finally, these data reinforce the role of microenvironments in leukaemia and suggest that macrophages are a potential target for the development of novel therapeutic strategies in T‐ALL.

The role of macrophages and osteoclasts in the progression of leukemia

“…The use of CSF-1R inhibitors in AML patients can inhibit the secretion of multiple cytokines in support cells and block their protective effects on AML cells. Similarly, our research also shows that targeting macrophages can delay the progression of ALL in mice [42]. Therefore, targeting CSF-1R combined with chemotherapeutic drugs can simultaneously kill leukemia cells, destroy the bone marrow microenvironment that they depend on for survival and enhance the antitumor effect.…”

“…Recent studies have found that TAMs also have a significant impact on leukemia, including AML, chronic lymphocytic leukemia (CLL) and ALL, and can promote the survival, growth and drug resistance of leukemia cells [40][41][42]. Yahya et al (2016) found that the proportion of CD163 + CD206 + M2-like macrophages in the bone marrow of AML patients was significantly higher than that of healthy volunteers.…”

The Role of Tumor-Associated Macrophages in Hematologic Malignancies

“…CSF-1R signaling is another important pathway for TAM recruitment and differentiation [ 74 , 160 , 161 , 162 ]. It was demonstrated that CSF-1R inhibition could block TAM polarization in T-ALL mouse models [ 160 ].…”

“…CSF-1R signaling is another important pathway for TAM recruitment and differentiation [ 74 , 160 , 161 , 162 ]. It was demonstrated that CSF-1R inhibition could block TAM polarization in T-ALL mouse models [ 160 ]. A treatment combination between vincristine and a CSF-1R inhibitor could improve survival in leukemic T-ALL mice compared to vincristine as a singleagent [ 160 ].…”

“…It was demonstrated that CSF-1R inhibition could block TAM polarization in T-ALL mouse models [ 160 ]. A treatment combination between vincristine and a CSF-1R inhibitor could improve survival in leukemic T-ALL mice compared to vincristine as a singleagent [ 160 ]. These findings were confirmed in CLL, in which pacritinib, a JAK2/FLT3 double inhibitor, blocked CSF-1R and was associated with TAM depletion and an improved survival [ 74 ].…”