Abstract 6811: IL-9 enhances lung tumor growth through intrinsic and ARG1-dependent transcriptomic changes in interstitial macrophages

Abstract A defining characteristic of cancer is its ability to evade detection by immune cells through the generation of a myeloid cell-dependent immunosuppressive tumor microenvironment. Arginine is utilized by Arginase 1 (ARG1) or nitric oxide synthase in tumor-associated macrophages to respectively elicit pro-tumor or anti-tumor activity. The balance between these enzymes is regulated by extracellular cytokines including Interleukin 9 (IL-9), a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab identified that IL-9 promotes tumor development in the lung by expanding interstitial macrophage populations and inducing ARG1. Lung tumor growth is attenuated in mice with myeloid cell deficiency of Arg1. Similarly, macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and alter macrophage populations in the lung toward an immunostimulatory phenotype. However, an understanding of the mechanism by which IL-9R/ARG1+ interstitial macrophages drive tumor progression remains incomplete. Here, using a B16F10 lung metastasis model in mixed-bone marrow chimeric mice, we demonstrate that IL-9-responsive interstitial macrophages are intrinsically altered at the transcriptomic level toward an ARG1-dependent immunosuppressive phenotype. Furthermore, our research shows that the absence of IL-9 signaling or ARG1 expression in macrophages has a notable impact on the levels of arginine and its metabolites in the lung tissue and bronchoalveolar lavage fluid of tumor-bearing mice. These alterations subsequently lead to an enhanced anti-tumoral immune response, reflected by changes in Interferon-gamma expression in both lung macrophages and T cells. Thus, our work suggests that the IL-9R/ARG1/interstitial macrophage axis promotes lung tumor development by altering intrinsic arginine metabolism and reprogramming immune cell populations toward an immunosuppressive phenotype. Citation Format: Anthony Cannon, Mark H. Kaplan. IL-9 enhances lung tumor growth through intrinsic and ARG1-dependent transcriptomic changes in interstitial macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6811.