title: 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.affiliation: Department of Immunology, Nankai University School of Medicine, Nankai University, Tianjin, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Yu
authors.forename: Suguang
authors.initials: S
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Zeng
authors.forename: Zhuohan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Guohui
authors.initials: G
authors.lastname: Jiao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Limin
authors.initials: L
authors.lastname: Cai
authors.forename: Rongcun
authors.initials: R
authors.lastname: Yang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000954:Antigens, Surface / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D039481:CD11b Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002277:Carcinoma / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor / Q000276:immunology / Q000637:transplantation; D004790:Enzyme Induction; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D019707:Receptors, Chemokine / Q000032:analysis; D013047:Specific Pathogen-Free Organisms
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D039481:CD11b Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; C503133:Gr-1 protein, mouse; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D019707:Receptors, Chemokine; D001119:Arginase