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; Mark H. Kaplan

doi:10.1038/s41467-022-31596-7

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

Pulmonary and Critical Care Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	3811
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31596-7
State	Published - Dec 2022

ASJC Scopus subject areas

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

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Fu, Y., Pajulas, A., Wang, J., Zhou, B., Cannon, A., Cheung, C. C. L., Zhang, J., Zhou, H., Fisher, A. J., Omstead, D. T., Khan, S., Han, L., Renauld, J. C., Paczesny, S., Gao, H., Liu, Y., Yang, L., Tighe, R. M., Licona-Limón, P., ... Kaplan, M. H. (2022). Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9. Nature communications, 13(1), [3811]. https://doi.org/10.1038/s41467-022-31596-7

Fu, Y, Pajulas, A, Wang, J, Zhou, B, Cannon, A, Cheung, CCL, Zhang, J, Zhou, H, Fisher, AJ, Omstead, DT, Khan, S, Han, L, Renauld, JC, Paczesny, S, Gao, H, Liu, Y, Yang, L, Tighe, RM, Licona-Limón, P, Flavell, RA, Takatsuka, S, Kitamura, D, Sun, J, Bilgicer, B, Sears, CR, Yang, K & Kaplan, MH 2022, 'Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9', Nature communications, vol. 13, no. 1, 3811. https://doi.org/10.1038/s41467-022-31596-7

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title = "Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9",

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.",

author = "Yongyao Fu and Abigail Pajulas and Jocelyn Wang and Baohua Zhou and Anthony Cannon and Cheung, {Cherry Cheuk Lam} and Jilu Zhang and Huaxin Zhou and Fisher, {Amanda Jo} and Omstead, {David T.} and Sabrina Khan and Lei Han and Renauld, {Jean Christophe} and Sophie Paczesny and Hongyu Gao and Yunlong Liu and Lei Yang and Tighe, {Robert M.} and Paula Licona-Lim{\'o}n and Flavell, {Richard A.} and Shogo Takatsuka and Daisuke Kitamura and Jie Sun and Basar Bilgicer and Sears, {Catherine R.} and Kai Yang and Kaplan, {Mark H.}",

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doi = "10.1038/s41467-022-31596-7",

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AU - Cannon, Anthony

AU - Cheung, Cherry Cheuk Lam

AU - Zhang, Jilu

AU - Zhou, Huaxin

AU - Fisher, Amanda Jo

AU - Omstead, David T.

AU - Khan, Sabrina

AU - Han, Lei

AU - Renauld, Jean Christophe

AU - Paczesny, Sophie

AU - Gao, Hongyu

AU - Liu, Yunlong

AU - Yang, Lei

AU - Tighe, Robert M.

AU - Licona-Limón, Paula

AU - Flavell, Richard A.

AU - Takatsuka, Shogo

AU - Kitamura, Daisuke

AU - Sun, Jie

AU - Bilgicer, Basar

AU - Sears, Catherine R.

AU - Yang, Kai

AU - Kaplan, Mark H.

PY - 2022/12

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N2 - 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.

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

Abstract

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