Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4+ T-cells and induction of antitumor CD8+ T-cell activity

Abstract

An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APCmin/+/Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4+RORγt+Foxp3−IL-17+ T-helper cell, CD4+RORγt+Foxp3+IL-17+ pathogenic T-regulatory cell and CD4+RORγt−Foxp3+IL-17− conventional T-regulatory cell numbers and a concurrent 2-fold enhancement in CD8+ T-cell activity in the colon. Selective subset depletion and functional blockade studies demonstrated that at steady-state CD4+RORγt+IL-17+ T-cell subsets and CD4+Foxp3+ cTreg supported tumorigenesis, whereas CD8+ cytotoxic T-lymphocytes impeded tumor progression following IL-10 therapy. Suppression of tumor growth by CD8+ T-cells was associated with enhanced tumor infiltration and cytotoxic granule exocytosis. These findings establish the utility of oral IL-10 as a potential new therapeutic in the management of colon cancer and shed light on the cellular mechanisms that underlie its antitumor activity.