IL-9 responsive macrophages utilize Arginase 1 to enhance lung tumor growth

Abstract In cancer, the immunosuppressive function of myeloid cells that support tumor progression is controlled by secreted factors in the tumor microenvironment. In the tumor microenvironment, arginine and arginine-derived metabolites have been demonstrated to be crucial factors in tumor development. Within macrophages, arginine metabolism influences the polarization of macrophages and therefore, tumor growth by eliciting an anti-tumoral or pro-tumoral phenotype. Interleukin 9 (IL-9) is a pleiotropic cytokine that signals through the IL-9 receptor (IL-9R) and can function as a positive or negative regulator in tumor immunity. Recently, our lab has demonstrated that IL-9 signaling promotes tumor progression in the lung by expanding pulmonary interstitial macrophage populations and inducing Arginase 1 (ARG1), an enzyme associated with pro-tumoral macrophage function, activity. However, the mechanism by which IL-9R/ARG1+ interstitial macrophages promote tumor development remains unknown. Here, using a B16F10 model of metastatic lung cancer, we demonstrate that knockdown of ARG1 using macrophage targeting Arg1siRNA containing nanoparticles results in altered pulmonary T-cell and macrophage proportions. Moreover, attenuation of IL-9 signaling and ARG1 expression in macrophages impacts arginine and arginine-derived metabolite concentration in lung tissue and BAL fluid which correlates with decreases in CD4+ T Cell exhaustion marker expression and a concomitant reduction in PDL1 expression on pulmonary interstitial macrophages in tumor-bearing mice. Thus, our work suggests that the IL-9R/ARG1 axis in macrophages is sufficient to alter arginine in the tumor microenvironment and promote tumor growth.