Abstract 4084: NKG2D receptor activation of mTOR and NFκB enhances antitumor immunity in effector CD8+ T cells

Abstract

Abstract To induce strong anti-tumor immune responses, naïve CD8+ T cells require stimulation through the TCR and costimulatory receptors. Each costimulatory molecule can have a unique effect on the function of T cells due to differential activation of downstream signaling pathways and gene expression. However, the effect of stimulating costimulatory receptors on activated T cells is still unclear. One costimulation receptor that is likely to be engaged in the tumor microenvironment is NKG2D since the ligands for this receptor are expressed on over 80% of tumors. In order to determine how activation of costimulatory receptors in the tumor microenvironment affects CD8+ T cell functions, this study investigated the differential activation of signaling pathways by two costimulatory receptors, CD28 and NKG2D. Specifically, this study focused on the activation of mTORC1 and mTORC2 along with NFκB, all of which have been shown to have important roles in anti-tumor functions of CD8+ T cells. Stimulation through the CD3 and NKG2D receptors differentially activated the mTOR and NFκB pathways compared to the other receptors in our study. Activation of CD8+ T cells through CD3 and NKG2D lead to increased phosphorylation of signal transduction pathway members upstream of mTOR, including AKT, p70 S6K, and GSK3β. Also, expression of genes upstream and downstream of mTORC1 and mTORC2 were differentially activated after stimulation through NKG2D, indicating that activation of mTOR pathways are altered after CD3/NKG2D stimulation as compared to stimulation through CD3 or CD3/CD28. In addition, IKKα, IκBα, and NFκB phosphorylation and IκBα degradation was increased after CD3/NKG2D stimulation. This increased activation of the NFκB pathway also lead to increased gene expression and secretion of pro-inflammatory cytokines, including IFN-alpha and IFN-gamma, and decreased gene expression and secretion of anti-inflammatory cytokines, including IL-10 and VEGF-alpha. Together, these data show that stimulation through NKG2D leads to the differential activation of signaling pathways and alters the anti-tumor functions of effector CD8+ T cells. Citation Format: Emily Whitman, Amorette E. Barber. NKG2D receptor activation of mTOR and NFκB enhances antitumor immunity in effector CD8+ T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4084. doi:10.1158/1538-7445.AM2014-4084