Abstract 4064: PD-1 blockade therapy enhances the antitumor effects of lymphodepletion and adoptive T cell transfer

Abstract Background: Lymphodepleting cytotoxic regimens, such as chemotherapy and radiotherapy, have shown the ability to enhance antitumor immunity. Although the mechanisms of antitumor effects augmentation in tumor-bearing hosts after lymphodepletion and T cell transfer have been intensively investigated, the influence of lymphodepletion followed by T cell transfer on immune checkpoint molecules (ICMs) expressed on tumor cells and immune cells remains to be elucidated. In the current study, we evaluated the effects of lymphodepletion and adoptive T cell transfer on ICMs in the tumor microenvironment. In addition, we investigated whether lymphodepletion and adoptive transfer of T cells augments antitumor effects of anti-PD-1 blockade therapy. Methods: B6 mice were inoculated subcutaneously with the MCA205 murine fibrosarcoma. On day 7, mice were lymphodepleted by sublethal irradiation with 500 cGy and were reconstituted intravenously with spleen cells from normal mice as a source of naïve T cells. These mice were injected intraperitoneally with anti-PD-1 mAb on days 7 and 14. On day 21, tumor tissues were harvested, and single cell suspensions were labeled with fluorophore-conjugated antibodies for FACS analyses. Results: The expressions of ICMs, including PD-L1, PD-1, TIGIT, TIM-3 and LAG-3, were upregulated on recipient CD4+ and CD8+ T cells in the tumor microenvironment. In contrast, these ICMs were significantly reduced in transferred donor T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Furthermore, transfer of both donor CD4+ and CD8+ T cells was responsible for this augmentation of antitumor effects. Conclusions: Our observations suggest that a possible mechanism of the antitumor effect augmentation mediated by lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. Blockade of PD-1 significantly enhanced the antitumor effects of lymphodepletion and T cell transfer. Citation Format: Satoshi Watanabe, Miho Takahashi, Ryo Suzuki, Masashi Arita, Ko Sato, Toshiya Fujisaki, Aya Ohtsubo, Satoshi Shoji, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Koichiro Nozaki, Tomohiro Tanaka, Rie Kondo, Yu Saida, Satoshi Hokari, Toshiyuki Koya, Toshiaki Kikuchi. PD-1 blockade therapy enhances the antitumor effects of lymphodepletion and adoptive T cell transfer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4064.