Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

Yongyao Fu, Abigail Pajulas, Jocelyn Wang, Baohua Zhou, Anthony Cannon, Cherry Cheuk Lam Cheung, Jilu Zhang, Huaxin Zhou, Amanda Jo Fisher, David T. Omstead, Sabrina Khan, Lei Han, Jean Christophe Renauld, Sophie Paczesny, Hongyu Gao, Yunlong Liu, Lei Yang, Robert M. Tighe, Paula Licona-Limón, Richard A. FlavellShogo Takatsuka, Daisuke Kitamura, Jie Sun, Basar Bilgicer, Catherine R. Sears, Kai Yang, Mark H. Kaplan

Research output: Contribution to journalArticlepeer-review


Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r−/− mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.

Original languageEnglish (US)
Article number3811
JournalNature communications
Issue number1
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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