Fu, YongyaoPajulas, AbigailWang, JocelynZhou, BaohuaCannon, AnthonyCheung, Cherry Cheuk LamZhang, JiluZhou, HuaxinFisher, Amanda JoOmstead, David T.Khan, SabrinaHan, LeiRenauld, Jean-ChristophePaczesny, SophieGao, HongyuLiu, YunlongYang, LeiTighe, Robert M.Licona-Limón, PaulaFlavell, Richard A.Takatsuka, ShogoKitamura, DaisukeSun, JieBilgicer, BasarSears, Catherine R.Yang, KaiKaplan, Mark H.2023-07-182023-07-182022-07-01Fu Y, Pajulas A, Wang J, et al. Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9. Nat Commun. 2022;13(1):3811. Published 2022 Jul 1. doi:10.1038/s41467-022-31596-7https://hdl.handle.net/1805/34454Although 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.en-USAttribution 4.0 InternationalInterleukinsTumour immunologyMonocytesMacrophagesCD4-positive T cellsArticle