Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity

  • Clin Cancer Res. 2019 Aug 1;25(15):4808-4819. doi: 10.1158/1078-0432.CCR-18-3991.
Tokiyoshi Tanegashima  1  2 ,  Yosuke Togashi  3 ,  Koichi Azuma  4 ,  Akihiko Kawahara  4 ,  Ko Ideguchi  5 ,  Daisuke Sugiyama  5 ,  Fumio Kinoshita  2  6 ,  Jun Akiba  7 ,  Eiji Kashiwagi  2 ,  Ario Takeuchi  2 ,  Takuma Irie  1 ,  Katsunori Tatsugami  2 ,  Tomoaki Hoshino  4 ,  Masatoshi Eto  2 ,  Hiroyoshi Nishikawa  3  5
Affiliations
  • 1. Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Kashiwa, Japan.
  • 2. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 3. Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Kashiwa, Japan. [email protected] [email protected].
  • 4. Department of Respiratory Medicine, Kurume University Hospital, Kurume, Japan.
  • 5. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 6. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 7. Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
PMID: 31076547 DOI: 10.1158/1078-0432.CCR-18-3991
Abstract

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.

Products