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. Flavell, Shogo Takatsuka, Daisuke Kitamura, Jie Sun, Basar Bilgicer, Catherine R. Sears, Kai Yang and Mark H. Kaplan ()
Additional contact information
Yongyao Fu: Indiana University School of Medicine
Abigail Pajulas: Indiana University School of Medicine
Jocelyn Wang: Indiana University School of Medicine
Baohua Zhou: Indiana University School of Medicine
Anthony Cannon: Indiana University School of Medicine
Cherry Cheuk Lam Cheung: Indiana University School of Medicine
Jilu Zhang: Indiana University School of Medicine
Huaxin Zhou: Indiana University School of Medicine
Amanda Jo Fisher: Indiana University School of Medicine
David T. Omstead: University of Notre Dame
Sabrina Khan: University of Notre Dame
Lei Han: Indiana University School of Medicine
Jean-Christophe Renauld: Université Catholique de Louvain
Sophie Paczesny: Medical University of South Carolina
Hongyu Gao: Indiana University School of Medicine
Yunlong Liu: Indiana University School of Medicine
Lei Yang: Indiana University School of Medicine
Robert M. Tighe: Duke University Medical Center
Paula Licona-Limón: Universidad Nacional Autónoma de México
Richard A. Flavell: Yale University School of Medicine
Shogo Takatsuka: Tokyo University of Science
Daisuke Kitamura: Tokyo University of Science
Jie Sun: Mayo Clinic
Basar Bilgicer: University of Notre Dame
Catherine R. Sears: Indiana University School of Medicine
Kai Yang: Indiana University School of Medicine
Mark H. Kaplan: Indiana University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31596-7

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