Purpose: Monocytes and their progeny are abundant constituents of the tumor microenvironment in lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). Monocyte-derived cells, including nurse-like cells (NLC) in CLL, promote lymphocyte proliferation and survival, confer resistance to chemotherapy, and are associated with more rapid disease progression. Colony-stimulating factor-1 receptor (CSF-1R) regulates the homeostatic survival of tissue-resident macrophages. Therefore, we sought to determine whether CSF-1R is similarly required for NLC survival.
Experimental design: CSF-1R expression by NLC was examined by flow cytometry and IHC. CSF-1R blocking studies were performed using an antagonistic mAb to examine its role in NLC generation and in CLL survival. A rational search strategy was performed to identify a novel tyrosine kinase inhibitor (TKI) targeting CSF-1R. The influence of TKI-mediated CSF-1R inhibition on NLC and CLL viability was examined.
Results: We demonstrated that the generation and survival of NLC in CLL is dependent upon CSF-1R signaling. CSF-1R blockade is associated with significant depletion of NLC and consequently inhibits CLL B-cell survival. We found that the JAK2/FLT3 inhibitor pacritinib suppresses CSF-1R signaling, thereby preventing the generation and survival of NLC and impairs CLL B-cell viability.
Conclusions: CSF-1R is a novel therapeutic target that may be exploited in lymphoproliferative disorders, like CLL, that are dependent upon lymphoma-associated macrophages. Clin Cancer Res; 22(24); 6118-28. ©2016 AACR.
©2016 American Association for Cancer Research.