Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of the Inflammatory Macrophage - T17-cell Axis

Abstract

Abstract Lung tumorigenesis has been linked to chronic type 17 inflammation in both murine models and patients. Interleukin-10 is a pleiotropic regulatory cytokine with profound inhibitory effects on type 17 responses. Intratracheal administration of a sustained-release IL-10 formulation resulted in suppression of tumor development in the LSL-K-ras spontaneous lung cancer model. Analysis of lung lymphocyte populations demonstrated that the antitumor activity of IL-10 was associated with a rapid 3 to 5-fold decline in IL-17-producing T-cell populations. Type 17 T-cells did not express detectable levels of IL-10RA suggesting that IL-10 was not directly acting on T-cells. In contrast, select myeloid cell populations including macrophages and a small subset of dendritic cells were found to express IL-10RA in the lung. In tumor-bearing control mice macrophages displayed a pro-inflammatory phenotype that reverted to a naive-like state following IL-10 treatment. Importantly, depletion of phagocytes resulted in a 3 to 5-fold decline in type 17 T-cell numbers with a concurrent 7-fold reduction in tumor burden. These findings demonstrate that in the LSL-K-ras model lung tumorigenesis is driven by the inflammatory macrophage - type 17 T-cell axis and that IL-10 abrogates this process via its direct activity on macrophages. Inhaled IL-10 formulations may be of utility in prophylaxis of lung cancer in high-risk patients.