JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Emily A. Irey, Chelsea M. Lassiter, Nicholas J. Brady, Pavlina Chuntova, Ying Wang, Todd P. Knutson, Christine Henzler, Thomas S. Chaffee, Rachel I. Vogel, Andrew C. Nelson, Michael A. Farrar, Kathryn L. Schwertfeger

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 protumorigenic factor cyclooxygenase-2 (COX-2), and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)12442-12451
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number25
StatePublished - Jun 18 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. The authors thank Dr. Jeffrey Rosen (Baylor College of Medicine) and Dr. Thomas Griffith (University of Minnesota) for providing cell lines; and Dr. Danielle Renner (University of Minnesota) for scientific discussions related to the manuscript and data analysis. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award UL1TR000114. Funding was also provided by NIH/National Institute of Allergy and Infectious Diseases T32AI007313 and NIH/National Cancer Institute F31CA220746 (to E.A.I.); NIH/National Cancer Institute T32CA009138 (to C.M.L.); and NIH/National Cancer Institute R01CA215052, NIH/Eunice Kennedy Shriver National Institute of Child Health and Development R01HD095858, and Department of Defense W81XWH-16-1-0034 funding (to K.L.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  • Breast cancer
  • Inflammation
  • JAK
  • Mammary tumor
  • STAT

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