Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment

Daisuke Umezu, Nana Okada, Yukimi Sakoda, Keishi Adachi, Toshiyasu Ojima, Hiroki Yamaue, Masatoshi Eto, Koji Tamada

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Although a role of PD-L1 in the suppression of anti-tumor immunity and its value as a predictive biomarker has been suggested by various preclinical and clinical studies, the precise mechanisms how PD-L1 and PD-L2, another ligand of PD-1, regulate anti-tumor immunity in the tumor microenvironment are yet to be fully explored. Here, we address this issue using PD-L1-deficient tumor cells, PD-L1-knockout (KO) mice, anti-PD-L1 monoclonal antibody (mAb), and anti-PD-L2 mAb. Firstly, PD-L1-deficient or competent tumor cells were inoculated into wild-type or PD-L1-KO mice. Results of tumor growth and mouse survival indicated that both tumor- and host-derived PD-L1 are functional to suppress anti-tumor immunity, while the former contributes predominantly than the latter. Experiments using bone marrow (BM) chimeric mice, generated by transferring PD-L1-KO BM cells into wild-type mice or vice versa, further suggested that PD-L1 expressed on BM-derived hematopoietic cells mediates the suppressive effects on anti-tumor immunity. Secondly, anti-PD-L2 mAb treatment demonstrated a profound synergy with anti-PD-L1 mAb therapy, whereas anti-PD-L2 mAb alone hardly induced any anti-tumor effects, suggesting that PD-L2’s function becomes evident when the effects of PD-L1 are abrogated by anti-PD-L1 mAb. Consistent with this notion, PD-L2 expression was upregulated on tumor-associated macrophages (TAM) when mice were treated with anti-PD-L1 mAb. Taken together, our study elucidated the importance of PD-L1 associated with tumor cells and non-tumor host cells, particularly BM-derived hematopoietic cells, as well as PD-L2 inducibly expressed on TAM in the suppression of anti-tumor immunity in the tumor microenvironment.

Original languageEnglish
Pages (from-to)201-211
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume68
Issue number2
DOIs
Publication statusPublished - Feb 13 2019

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Tumor Microenvironment
Immunity
Neoplasms
Monoclonal Antibodies
Programmed Cell Death 1 Ligand 2 Protein
Bone Marrow Cells
Bone Marrow
Macrophages
Knockout Mice

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. / Umezu, Daisuke; Okada, Nana; Sakoda, Yukimi; Adachi, Keishi; Ojima, Toshiyasu; Yamaue, Hiroki; Eto, Masatoshi; Tamada, Koji.

In: Cancer Immunology, Immunotherapy, Vol. 68, No. 2, 13.02.2019, p. 201-211.

Research output: Contribution to journalArticle

Umezu, Daisuke ; Okada, Nana ; Sakoda, Yukimi ; Adachi, Keishi ; Ojima, Toshiyasu ; Yamaue, Hiroki ; Eto, Masatoshi ; Tamada, Koji. / Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. In: Cancer Immunology, Immunotherapy. 2019 ; Vol. 68, No. 2. pp. 201-211.
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