Microenvironment and Immunology CancerStem-likeCellsDerived fromChemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells fromCD14þmonocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-R– specific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5þ CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors. Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumorassociated CSF1 receptorþ M2 macrophages in patients with non–small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments. Cancer Res; 74(10);