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 journalArticle

4 Scopus citations

Abstract

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
Volume116
Issue number25
DOIs
StatePublished - Jun 18 2019

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Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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