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

Fu, Yongyao; Pajulas, Abigail; Wang, Jocelyn; Zhou, Baohua; Cannon, Anthony; Cheung, Cherry Cheuk Lam; Zhang, Jilu; Zhou, Huaxin; Fisher, Amanda Jo; Omstead, David T; Khan, Sabrina; Han, Lei; Renauld, Jean-Christophe; Paczesny, Sophie; Gao, Hongyu; Liu, Yunlong; Yang, Lei; Tighe, Robert M; Licona-Limon, Paula; Flavell, Richard A; Takatsuka, Shogo; Kitamura, Daisuke; Sun, Jie; Bilgicer, Basar; Sears, Catherine R; Yang, Kai; Kaplan, Mark H (2022). Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9. Nat Commun 13 (1)

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.



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