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

研究成果: ジャーナルへの寄稿記事

1 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)4808-4819
ページ数12
ジャーナルClinical Cancer Research
25
発行部数15
DOI
出版物ステータス出版済み - 8 1 2019

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Immunity
Neoplasms
Animal Models
Renal Cell Carcinoma
Squamous Cell Carcinoma
T-Lymphocytes
Lung
Tumor Microenvironment
Atlases
Neoplasm Antigens
Immunosuppressive Agents
Immunotherapy
Research Design
Therapeutics
Genome
Lymphocytes
Phenotype
Gene Expression
Cell Line
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Tanegashima, T., Togashi, Y., Azuma, K., Kawahara, A., Ideguchi, K., Sugiyama, D., ... Nishikawa, H. (2019). Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. Clinical Cancer Research, 25(15), 4808-4819. https://doi.org/10.1158/1078-0432.CCR-18-3991

Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. / Tanegashima, Tokiyoshi; Togashi, Yosuke; Azuma, Koichi; Kawahara, Akihiko; Ideguchi, Ko; Sugiyama, Daisuke; Kinoshita, Fumio; Akiba, Jun; Kashiwagi, Eiji; takeuchi, ario; Irie, Takuma; Tatsugami, Katsunori; Hoshino, Tomoaki; Eto, Masatoshi; Nishikawa, Hiroyoshi.

:: Clinical Cancer Research, 巻 25, 番号 15, 01.08.2019, p. 4808-4819.

研究成果: ジャーナルへの寄稿記事

Tanegashima, T, Togashi, Y, Azuma, K, Kawahara, A, Ideguchi, K, Sugiyama, D, Kinoshita, F, Akiba, J, Kashiwagi, E, takeuchi, A, Irie, T, Tatsugami, K, Hoshino, T, Eto, M & Nishikawa, H 2019, 'Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity', Clinical Cancer Research, 巻. 25, 番号 15, pp. 4808-4819. https://doi.org/10.1158/1078-0432.CCR-18-3991
Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D その他. Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. Clinical Cancer Research. 2019 8 1;25(15):4808-4819. https://doi.org/10.1158/1078-0432.CCR-18-3991
Tanegashima, Tokiyoshi ; Togashi, Yosuke ; Azuma, Koichi ; Kawahara, Akihiko ; Ideguchi, Ko ; Sugiyama, Daisuke ; Kinoshita, Fumio ; Akiba, Jun ; Kashiwagi, Eiji ; takeuchi, ario ; Irie, Takuma ; Tatsugami, Katsunori ; Hoshino, Tomoaki ; Eto, Masatoshi ; Nishikawa, Hiroyoshi. / Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. :: Clinical Cancer Research. 2019 ; 巻 25, 番号 15. pp. 4808-4819.
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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.",
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AU - Tanegashima, Tokiyoshi

AU - Togashi, Yosuke

AU - Azuma, Koichi

AU - Kawahara, Akihiko

AU - Ideguchi, Ko

AU - Sugiyama, Daisuke

AU - Kinoshita, Fumio

AU - Akiba, Jun

AU - Kashiwagi, Eiji

AU - takeuchi, ario

AU - Irie, Takuma

AU - Tatsugami, Katsunori

AU - Hoshino, Tomoaki

AU - Eto, Masatoshi

AU - Nishikawa, Hiroyoshi

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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