Age-associated increase of IL-6 dampens anti-tumor immune responses through attenuating Th1 differentiation of tumor-specific CD4 T cells (TUM7P.928)

Abstract

Abstract With age immune function progressively decreases and pro-inflammatory status is concomitantly developed. We focused on the impact of this inflammatory environment on tumor-specific CD4 T cells. We demonstrated that in contrast to tumor elimination in young hosts, adoptive transfer of OVA-specific young CD4 T cells and vaccination with OVA peptide-pulsed DC failed to induce efficient regression of OVA-expressing tumor cells in aged hosts. This was consistent with the result that in aged mice generation of tumor-specific Th1 cells was significantly attenuated. Interestingly, a blockade of IL-6 signaling partially restored Th1 differentiation of donor CD4 T cells and elicited tumor regression in aged hosts, but did not alter their expansion, IL-2 or IL-17A production. Furthermore, in vitro analyses revealed that IL-6 directly acted on CD4 T cells to attenuate Th1 differentiation. IL-6 blockade also restored the defect in an ability of tumor-specific CD4 T cells to promote anti-tumor CD8 T cells induction in aged mice. These results were confirmed by aged IL-6-deficient mice. However, the Th1-mediated help for tumor-specific CD8 T cells was not observed in aged mice when IFN-γ-deficient CD4 T cells were transferred into anti-IL-6 Ab-treated mice. These results imply that systemic increase of IL-6 is an extrinsic factor counteracting tumor-specific Th1 differentiation, and is responsible for the age-associated defect in mounting protective anti-tumor immunity in aged individuals.