GSE131300
JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors
Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the pro-tumorigenic factor cyclooxygenase-2 (COX-2) and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a novel mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment. Overall design: Primary human macrophages were treated with breast tumor cell (MCF7, MDA-MB-231, or control) conditioned medium, in combination with ruxolitinib (or control), and processed for gene expression analysis in triplicate. Bone marrow derived macrophages from STAT3 wild type or STAT3 conditional knockout mice were extracted and were processed for gene expression analysis in triplicate.