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

• Published in: Nature communications Vol. 13; no. 1; pp. 3811 - 19
• Main Authors: 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-Limón, Paula, Flavell, Richard A., Takatsuka, Shogo, Kitamura, Daisuke, Sun, Jie, Bilgicer, Basar, Sears, Catherine R., Yang, Kai, Kaplan, Mark H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/21; 13/31; 38; 38/91; 631/250/127/1213; 631/250/1619/554/1898; 631/250/2504/342; 631/250/580; 64; 64/60; Adoptive transfer; Animal models; Animals; Anticancer properties; Antitumor agents; Arginase; Carcinogenesis - metabolism; CD11c antigen; CD4 antigen; Cell culture; Cytokines; Humanities and Social Sciences; Interleukin 9; Interleukin 9 receptors; Interleukin-9 - genetics; Interleukin-9 - metabolism; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Macrophages - pathology; Macrophages, Alveolar - metabolism; Mice; multidisciplinary; Nanoparticles; Science; Science (multidisciplinary); Signaling; Therapeutic applications; Therapeutic targets; Tumor microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31596-7

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. The role of IL-9 in the tumor microenvironment and its effects on macrophages remains unclear. Here, the authors show that IL-9 promotes the expansion of pulmonary macrophages and that targeting the IL-9R/arginase 1 axis restricts tumor growth, thus identifying this cytokine pathway as a potential therapeutic target.