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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.

SUBMITTER: Fu Y

PROVIDER: S-EPMC9249769 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Fu Yongyao Y Pajulas Abigail A Wang Jocelyn J Zhou Baohua B Cannon Anthony A Cheung Cherry Cheuk Lam CCL Zhang Jilu J Zhou Huaxin H Fisher Amanda Jo AJ Omstead David T DT Khan Sabrina S Han Lei L Renauld Jean-Christophe JC Paczesny Sophie S Gao Hongyu H Liu Yunlong Y Yang Lei L Tighe Robert M RM Licona-Limón Paula P Flavell Richard A RA Takatsuka Shogo S Kitamura Daisuke D Sun Jie J Bilgicer Basar B Sears Catherine R CR Yang Kai K Kaplan Mark H MH

Nature communications 20220701 1

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 ...[more]

PMID: 35778404

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Project description:Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.

Dataset Information

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

Publications

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

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