Abstract 2818: Dendritic cell vaccination and regulatory T-cell depletion augment antitumor immunity after cytotoxic therapy

Abstract

Abstract The ability of lymphodepleting cytotoxic regimens to augment antitumor immune responses has been well established. We and others have previously reported that naïve T cells, as well as effector T cells, transferred into lymphopenic tumor-bearing mice acquire memory-like phenotypes and show antitumor effects. The transfer of naïve T cells into irradiated lymphopenic mice inhibited tumor progression. Further analyses revealed that the transfer of CD4+ naïve T cells was essential for this augmentation of antitumor immunity after lymphodepletion. To enhance the antitumor efficacy of lymphodepletion and transfer of naïve T cells, we have tested anti-CTLA-4 mAbs and anti-CD25 mAbs for depletion of regulatory T cells. Mice were irradiated with 500 cGy to deplete lymphocytes and were transferred i.v. with T cells (2 x 107). On the same day, mice were inoculated with MCA205 tumor cells (1 x 105) followed by the injection of anti-CTLA-4 mAbs (UC10) or the injection of anti-CD25 mAbs (PC61). Although the injection of anti-CTLA-4 mAbs showed minimal augmentation of the antitumor effects of the combination of lymphodepletion and naïve T cell transfer, anti-CD25 mAbs significantly enhanced antitumor immune responses. Next, we evaluated whether dendritic cell vaccination augments this combination therapy. Different from previous experiments, 3-day tumor-bearing mice were irradiated and reconstituted with T cells. Dendritic cells were generated from bone marrow of naïve mice and were co-cultured with irradiated MCA205 tumor cells followed by stimulation with agonistic anti-CD40 mAbs. We found that dendritic cell vaccination significantly inhibited tumor growth in irradiated reconstituted mice. Previously, we reported that a significant increase of CD4+CD25+Foxp3+ regulatory T cells in irradiated mice. We demonstrated that these radio-resistant regulatory T cells from irradiated recipient mice suppressed the development of antitumor immunity. To clarify the roles of other recipient cells in antitumor immunity during recovery from lymphopenia, Rag-2 knockout mice were irradiated and reconstituted with T cells. These mice were then inoculated MCA205 tumor cells. In Rag-2 knockout mice, antitumor effects were not observed after lymphodepletion and reconstitution. These findings indicate that recipient T cells or B cells were required to augment antitumor immunity in lymphopenic mice in our model. Citation Format: Tomohiro Tanaka, Satoshi Watanabe, Ko Sato, Yu Saida, Junko Baba, Koichiro Nozaki, Daisuke Ishikawa, Natsue Igarashi, Satoshi Shoji, Masaaki Okajima, Satoru Miura, Junta Tanaka, Hiroshi Tanaka, Hiroshi Kagamu, Hirohisa Yoshizawa, Ichiei Narita. Dendritic cell vaccination and regulatory T-cell depletion augment antitumor immunity after cytotoxic therapy. [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 2818. doi:10.1158/1538-7445.AM2014-2818