Abstract 4570: Intratumoral IFN-α gene transfer reduces trafficking of Tregs into tumor by inhibition of CCL17 expression

Abstract

Abstract Type I interferon (IFN) is a pleiotropic cytokine regulating the cancer cell death and immune response. IFN-α can effectively induce an antitumor immunity by the activation of tumor-specific T cells and maturation of dendritic cells in various animal models. It is widely known that an induction of tolerance by the tumor is one of the critical mechanisms involved in tumor progression and resistance for immune therapy. Extensive studies have shown that CD4+Foxp3+ regulatory T cells (Tregs) are critical in controlling antitumor immune responses in the tumor microenvironment. Since the effect of type I IFN on an immunotolerant microenvironment is unknown, we investigated the immunological effects of intratumoral IFN-α gene transfer on tumor-infiltrating Tregs in a mouse model. Here, to examine whether the expression of IFN-α affects the immunotolerant microenvironment in tumors, CT26 murine colon cancer tumors were directly injected once with 1 x 108 PFU of IFN-α-expressing adenovirus (Ad-mIFN). The injection of Ad-mIFN significantly suppressed the tumor growth. We found that intratumoral IFN-α gene transfer significantly decreased the frequency of Tregs per CD4+ T cells in tumors compared with control vector injection. We hypothesized that Treg-homing cytokines such as CCL17 and CCL22 cytokines are involved in the reduction of tumor-infiltrating Tregs by the Ad-mIFN injection. The IFN-α expression significantly suppressed of CCL17 and CCL22 expression of tumors, and the expression of CCR4 and CCR5 expression on Tregs was not changed. IFN-α protein significantly suppressed CCL17 of CT26 cells in vitro in a dose-dependent manner. Then, we constructed CCL17 shRNA-transduced CT26 cells (CT26shCCL17) to examine the immunological role of CCL17 in vivo. The frequency of Tregs per CD4+ T cells was significantly reduced in subcutaneous tumors of CT26shCCL17 cells (25.9 %), and tumor growth was inhibited compared with that of control shRNA-transduced CT26 cells (39.4%), suggesting CCL17 has an important role to migrate Tregs into tumors. The study demonstrated that IFN-α gene delivery creates an environment strongly supporting the enhancement of antitumor immunity through the suppression of Tregs. Citation Format: Kazunori Aoki, Chihiro Shibasaki, Hisayoshi Hashimoto, Kenta Narumi, Chie Kudo. Intratumoral IFN-α gene transfer reduces trafficking of Tregs into tumor by inhibition of CCL17 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4570. doi:10.1158/1538-7445.AM2017-4570