Abstract LB-207: IFN-Γ directly regulates ifi202B expression to maintain CTL proliferation potential and tumor rejection efficacy

Abstract

Abstract A common procedure in human cytotoxic T lymphocyte (CTL) adoptive transfer cancer immunotherapy is to propagate tumor-specific CTLs in vitro using anti-CD3 mAb prior to transfer. One of the major impediments of CTL adoptive cancer immunotherapy is lack of CTL persistence in the tumor-bearing host after adoptive transfer. Therefore, maintaining CTL proliferation and persistence in the tumor microenvironment is of great significance in cancer immunotherapy. In this study, we observed that stimulation of tumor-specific CTLs with anti-CD3 mAb results in loss of proliferative potential and poor tumor-rejection efficacy in vivo, whereas, stimulation with tumor-specific antigen maintains CTL proliferative potential and persistence, leading to potent tumor rejection in an experimental lung metastasis mouse model. Analysis of genome-wide gene expression profile revealed that ifi202B, a gene with known function in regulating T cell proliferation and apoptosis, was dramatically up-regulated in antigen-stimulated but not in anti-CD3 mAb-stimulated CTLs. Furthermore, although both antigen- and anti-CD3 mAb-stimulated CTLs express similar level of IFN-Γ receptor, antigen stimulation led to rapid activation of STAT1, a key mediator of the IFN-Γ signaling pathway, whereas anti-CD3 mAb stimulation failed to activate STAT1. We further demonstrated that activated STAT1 binds to the promoter of ifi202b gene in T cells. Taken together, these observations suggest that IFN-Γ produced by the activated CTLs and the IFN-Γ signaling pathway plays a critical role in maintaining CTL proliferation and persistence in the tumor microenvironment through regulating ifi202B. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-207.