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

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 ar...

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Published in:	Cancer Immunology, Immunotherapy Vol. 68; no. 2; pp. 201 - 211
Main Authors:	Umezu, Daisuke, Okada, Nana, Sakoda, Yukimi, Adachi, Keishi, Ojima, Toshiyasu, Yamaue, Hiroki, Eto, Masatoshi, Tamada, Koji
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2019 Springer Nature B.V
Subjects:	Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology B7-H1 Antigen - genetics B7-H1 Antigen - immunology B7-H1 Antigen - metabolism Bone marrow Bone Marrow Cells - immunology Cancer Research Cell Line, Tumor Immunology Macrophages Medicine Medicine & Public Health Mice, Inbred C57BL Mice, Knockout Monoclonal antibodies Neoplasms, Experimental - genetics Neoplasms, Experimental - immunology Neoplasms, Experimental - metabolism Oncology Original Original Article PD-1 protein PD-L1 protein Programmed Cell Death 1 Ligand 2 Protein - genetics Programmed Cell Death 1 Ligand 2 Protein - immunology Programmed Cell Death 1 Ligand 2 Protein - metabolism Survival Analysis Tumor Burden - drug effects Tumor Burden - genetics Tumor Burden - immunology Tumor cells Tumor Microenvironment - drug effects Tumor Microenvironment - genetics Tumor Microenvironment - immunology PD-L1 PD-L2 Tumor microenvironment Tumor-associated macrophages
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0340-7004 1432-0851
DOI:	10.1007/s00262-018-2263-4