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posted on 2023-03-31, 20:43 authored by Tokiyoshi Tanegashima, Yosuke Togashi, Koichi Azuma, Akihiko Kawahara, Ko Ideguchi, Daisuke Sugiyama, Fumio Kinoshita, Jun Akiba, Eiji Kashiwagi, Ario Takeuchi, Takuma Irie, Katsunori Tatsugami, Tomoaki Hoshino, Masatoshi Eto, Hiroyoshi Nishikawa In vitro PD-L2 expression in MC38, CT26-NY-ESO-1, B16-F10, Renca, CMS5a and A20 treated with or without IFN-α, IFN-β, IFN-γ, TNF-α, IL-2, IL-4, TGF-β1 or GM-CSF.
Funding
Ministry of Education, Culture, Sports, Science and Technology of Japan
Japan Agency for Medical Research and Development
National Cancer Center Research and Development Fund
Naito Foundation
Takeda Foundation
Kobayashi Foundation for Cancer Research
History
ARTICLE ABSTRACT
To evaluate the detailed immunosuppressive role(s) of PD-L2 given that its detailed role(s) remains unclear in PD-1 signal blockade therapy in animal models and humans.
We generated mouse cell lines harboring various status of PD-L1/PD-L2 and evaluated the tumor growth and phenotypes of tumor-infiltrated lymphocytes using several PD-1 signal blockades in animal models. In humans, the correlation between immune-related gene expression and CD274 (encoding PD-L1) or PDCD1LG2 (encoding PD-L2) was investigated using The Cancer Genome Atlas (TCGA) datasets. In addition, PD-L1 or PD-L2 expression in tumor cells and CD8+ T-cell infiltration were assessed by IHC.
In animal models, we showed that PD-L2 expression alone or simultaneously expressed with PD-L1 in tumor cells significantly suppressed antitumor immune responses, such as tumor antigen–specific CD8+ T cells, and was involved in the resistance to treatment with anti-PD-L1 mAb alone. This resistance was overcome by anti-PD-1 mAb or combined treatment with anti-PD-L2 mAb. In clinical settings, antitumor immune responses were significantly correlated with PD-L2 expression in the tumor microenvironment in renal cell carcinoma (RCC) and lung squamous cell carcinoma (LUSC).
We propose that PD-L2 as well as PD-L1 play important roles in evading antitumor immunity, suggesting that PD-1/PD-L2 blockade must be considered for optimal immunotherapy in PD-L2–expressing cancers, such as RCC and LUSC.
