Myeloid dendritic cell-specific mTORC2 deficiency enhances Th1 and Th17 cell responses and inhibits B16 melanoma growth (TUM6P.959)

Abstract

Abstract The mechanistic/mammalian target of rapamycin (mTOR) is a key integrative kinase that functions in at least two independent complexes: mTOR complex (C)1 and mTORC2. While mTORC2 in T cells promotes Th2 differentiation, its immunologic function in dendritic cells (DC) is largely unknown. We defined the role of rictor, a key mTORC2 component, in myeloid DC and their ability to polarize allogeneic T cells. When stimulated with TLR ligands, bone marrow-derived DC generated from conditional Rictor knockouts displayed lower co-inhibitory B7-H1 (CD274) molecule expression, enhanced IL-12p70, IL-23, IL-6 and TNFα production and augmented allogeneic T cell stimulatory ability. Analysis of antigen-specific CD4+ T cells after activation by Rictor-/- DC in vivo revealed significant expansion of IFN-γ+ and IL-17+, but not IL-10+ or CD4+Foxp3+ T cells. Consistent with this pro-inflammatory effect, intratumoral injection of Rictor-/- DC markedly slowed B16 melanoma growth in B6 WT mice compared to control DC (p<0.05), promoting enhancement of CD4+IL-17+ and CD8+INFγ+ T cells in the spleens of Rictor-/- DC treated animals compared with controls. These data indicate that DC lacking mTORC2 activity exhibit an enhanced pro-inflammatory profile with ability to promote Th1/Th17 responses and slowed melanoma progression versus control DC. Therefore, targeting mTORC2 provides new insight into molecular regulation of DC function with therapeutic implications for cancer.