Abstract 3206: Programmed death receptor-1/programmed death receptor ligand-1 blockade improves priming of antitumor effector T cells after cytotoxic therapies

Cytotoxic lymphodepletion therapies, such as chemotherapy and radiotherapy, have been established to augment antitumor immunity. Naive T cellselicit effector-like phenotypes and functions during recovery from lymphopenia. We and others have repeatedly demonstrated that transfer of naive T cellsinto lymphopenic-tumor bearing mice delayed tumor growth. This enhancement of naive T cellsis required an activation through T-cell receptor (TCR). Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 ( PD-L1) blockadetherapy has been demonstrated to augment antitumor immunity. Previous studies have shown that PD-1/ PD-L1 blockadetherapy stimulates or restores the function of antitumor T cells in the effectorphase. Because engagement of programmed death receptor-1 (PD-1) by ligand suppresses TCR signaling and inhibits T cell activation and function, there is a possibility that PD-1 regulates activation of T cells during recovery from lymphopenia after cytotoxic therapies. In the current study, we transferred naive T cellsinto tumor-bearing mice following whole-body irradiation for lymphodepletion. These mice were further treated with anti-PD-1 antibodies. PD-1/ PD-L1 blockadetherapy after lymphodepletion significantly suppressed tumor progression. Next, we tested several kinds of cytotoxic agents to induce lymphopenia in mice. We found that the kind of cytotoxic agents affected the augmentation of antitumor efficacies of PD-1/ PD-L1 blockade. Analyses of tumor-draining lymph-nodes (TDLNs) revealed that the number of tumor-specific effectorT cells was significantly increased in mice treated with anti-PD-1 antibodies. By contrast, the number of effectorT cells in spleens was not increased by PD-1/ PD-L1 blockadetherapy. These results indicate that PD-1 regulates a priming of antitumor effectorT cells in TDLNs after cytotoxic lymphodepletion therapies. PD-1/ PD-L1 blockadetherapy is able to enhance antitumor T cell responses not only in the effectorphase but also in the priming phase. Citation Format: Miho Takahashi, Satoshi Watanabe, Ko Sato, Tomohiro Tanaka, Yu Saida, Junko Baba, Aya Ohtsubo, Miyuki Sato, Rie Kondo, Masaaki Okajima, Junta Tanaka, Hiroshi Kagamu, Hirohisa Yoshizawa, Toshiaki Kikuchi. Programmed death receptor-1/programmed death receptor ligand-1 blockadeimproves priming of antitumor effectorT cells after cytotoxic therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3206.