Chimeric PD‑1 receptor redirects primary T cells against childhood solid tumors but not to PD‑1 ligand‑positive CD80‑coexpressing cells

Shin,Chansu; Imamura,Masaru; Kasahara,Yasushi; Suzuki,Yuko; Baba,Minori; Kubo,Nobuhiro; Hosokai,Ryosuke; Iwabuchi,Haruko; Murayama,Yudai; Kawashima,Hiroyuki; Ogose,Akira; Mihara,Keichiro; Saitoh,Akihiko; Imai,Chihaya

doi:10.3892/mmr.2025.13608

Chimeric PD‑1 receptor redirects primary T cells against childhood solid tumors but not to PD‑1 ligand‑positive CD80‑coexpressing cells

Authors:
- Chansu Shin
- Masaru Imamura
- Yasushi Kasahara
- Yuko Suzuki
- Minori Baba
- Nobuhiro Kubo
- Ryosuke Hosokai
- Haruko Iwabuchi
- Yudai Murayama
- Hiroyuki Kawashima
- Akira Ogose
- Keichiro Mihara
- Akihiko Saitoh
- Chihaya Imai
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Affiliations: Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951‑8510, Japan, Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata 951‑8510, Japan, Department of Orthopedic Surgery, Uonuma Kikan Hospital, Minamiuonuma, Niigata 949‑7302, Japan, International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Aichi 470‑1192, Japan
Published online on: July 7, 2025 https://doi.org/10.3892/mmr.2025.13608
Article Number: 243
Copyright: © Shin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The clinical application of T cells engineered with chimeric antigen receptors (CARs) for solid tumors is challenging. A major reason for this involves tumor immune evasion mechanisms, including the high expression of immune checkpoint molecules, such as the programmed death 1 (PD‑1) ligands PD‑L1 and PD‑L2. The inducible expression of PD‑L1 in tumors has been observed after CAR‑T‑cell infusion, even in tumors natively not expressing PD‑L1. Furthermore, numerous types of pediatric cancer do not have suitable targets for CAR‑T‑cell therapy. Therefore, the present study aimed to develop novel CAR‑T cells that target PD‑L1 and PD‑L2, and to evaluate their efficacy against pediatric solid tumors. A novel CAR harboring the immunoglobulin V‑set domain of the human PD‑1 receptor as an antigen binding site (PD‑1 CAR‑T) was developed without using a single‑chain variable fragment. PD‑1 CAR‑T cells were successfully manufactured by adding an anti‑PD‑1 antibody, nivolumab, to the ex vivo expansion culture to prevent fratricide during the manufacturing process due to the inducible expression of PD‑L1 in activated human T cells. The expression of PD‑L1 (and PD‑L2 to a lesser extent) was revealed to be highly upregulated in various pediatric solid tumor cells, which displayed no or very low expression initially, on in vitro exposure to interferon‑γ and/or tumor necrosis factor‑α, which are cytokines secreted by tumor‑infiltrating T cells. Furthermore, PD‑1 CAR-T cells exhibited strong cytotoxic activity against pediatric solid tumor cells expressing PD‑L1 and PD‑L2. Conversely, the effect of PD‑1 CAR‑T cells was significantly attenuated against PD‑L1‑positive cells coexpressing CD80, suggesting that the toxicity of PD‑1 CAR‑T cells to normal immune cells, including antigen presenting cells, can be minimized. In conclusion, PD‑1 ligands are promising therapeutic targets for pediatric solid tumors. PD‑1 CAR‑T cells, either alone or in combination with CAR‑T cells with other targets, represent a potential treatment option for solid tumors.

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