Macrophage-intrinsic and IL-9-dependent arginine metabolism promotes lung tumor growth

Tumor-associated macrophages are an abundant, tumor-infiltrating cell population that supports the evasion of tumor cells from anti-tumoral immune cell detection by generating an immunosuppressive tumor-immune microenvironment (TIME). The immunosuppressive function of macrophages is dictated by the cytokine environment. IL-9 is a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab previously identified a pro-tumoral role of IL-9 by expanding lung interstitial macrophage populations and inducing the expression of arginase 1 (ARG1) to enhance tumor growth. However, the underlying mechanism by which IL-9R/ARG1+ interstitial macrophages promote tumor progression remains incomplete. Here, we demonstrate that macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and reduce pro-tumor arginine-derived metabolite production. Furthermore, using bulk RNA sequencing of lung macrophages isolated from Il9r-/-:WT mixed-bone marrow chimeric mice, we demonstrate that IL-9 intrinsically alters the transcriptomic landscape of lung interstitial macrophages. Mechanistically, IL-9 promotes intrinsic Arg1 expression through an IRF4-dependent regulatory pathway and modulates arginine and polyamine concentration within interstitial macrophages and lung tissue, resulting in increased lung tumor growth and altered macrophage phenotypes. Thus, our work defines a pro-tumor mechanism of IL-9-responsive macrophages mediated by altered intrinsic arginine metabolism in lung interstitial macrophages that enhances lung tumor growth.