Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity

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

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)


Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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.

Original languageEnglish
Pages (from-to)4808-4819
Number of pages12
JournalClinical Cancer Research
Issue number15
Publication statusPublished - Aug 1 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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