Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells.

Abstract	An elevated number of Gr-1(+)CD11b(+) myeloid-derived suppression cells (MDSCs) has been described in mice and human bearing tumor and associated with immune suppression. Arginase I production by MDSCs in the tumor environment may be a central mechanism for immunosuppression and tumor evasion. In this study and before, we found that Gr-1(+)CD11b(+) MDSCs from ascites and spleen of mice bearing ovarian 18D carcinoma express a high level of PD-1, CTLA-4, B7-H1 and CD80 while other co-stimulatory molecules, namely CD40, B7-DC and CD86 are not detected. Further studies showed that PD-1 and CTLA-4 on the Gr-1(+)CD11b(+) MDSCs regulated the activity and expression of arginase I. The blockage and silencing of PD-1, CTLA-4 or both PD-1 and CTLA4 molecules could significantly reduce arginase I activity and expression induced with tumor-associated factor. Similar results were also observed while their ligands B7-H1 and/or CD80 were blocked or silenced. Furthermore, CD80 deficiency also decreased the arginase I expression and activity. Antibody blockade or silencing of PD-1, CTLA-4 or both reduced the suppressive potential of PD-1+CTLA-4+MDSCs. Blockade of PD-1, CTLA-4 or both also slowed tumor growth and improved the survival rate of tumor-bearing mice. Thus, there may exist a coinhibitory and costimulatory molecules-based immuno-regulating net among MDSCs.
Authors	Yu Liu, Yinyan Yu, Suguang Yang, Bin Zeng, Zhuohan Zhang, Guohui Jiao, Yuan Zhang, Limin Cai, Rongcun Yang
Journal	Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 58 Issue 5 Pg. 687-97 (May 2009) ISSN: 1432-0851 [Electronic] Germany
PMID	18828017 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antibodies, Monoclonal Antigens, CD Antigens, Surface Apoptosis Regulatory Proteins B7-1 Antigen B7-H1 Antigen CD11b Antigen CTLA-4 Antigen CTLA4 protein, human Cd274 protein, mouse Ctla4 protein, mouse Gr-1 protein, mouse Membrane Glycoproteins Neoplasm Proteins Pdcd1 protein, mouse Peptides Programmed Cell Death 1 Receptor RNA, Small Interfering Receptors, Chemokine Arginase
Topics	Animals Antibodies, Monoclonal (pharmacology) Antigens, CD (genetics, physiology) Antigens, Surface (analysis, genetics, physiology) Apoptosis Regulatory Proteins (analysis, genetics, physiology) Arginase (biosynthesis, genetics) B7-1 Antigen (immunology) B7-H1 Antigen CD11b Antigen (analysis) CD8-Positive T-Lymphocytes (immunology) CTLA-4 Antigen Carcinoma (enzymology, immunology, pathology) Cell Line, Tumor (immunology, transplantation) Enzyme Induction Female Male Membrane Glycoproteins (immunology) Mice Mice, Inbred C57BL Neoplasm Proteins (biosynthesis, genetics, physiology) Ovarian Neoplasms (enzymology, immunology, pathology) Peptides (immunology) Programmed Cell Death 1 Receptor RNA Interference RNA, Small Interfering (genetics, physiology) Receptors, Chemokine (analysis) Specific Pathogen-Free Organisms

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