Article ; Online: Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells.
Cancer immunology, immunotherapy : CII
2008 Volume 58, Issue 5, Page(s) 687–697
Abstract: ... regulated the activity and expression of arginase I. The blockage and silencing of PD-1, CTLA-4 or both PD-1 ... 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 ...
| 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. |
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| MeSH term(s) | Animals ; Antibodies, Monoclonal/pharmacology ; Antigens, CD/genetics ; Antigens, CD/physiology ; Antigens, Surface/analysis ; Antigens, Surface/genetics ; Antigens, Surface/physiology ; Apoptosis Regulatory Proteins/analysis ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/physiology ; Arginase/biosynthesis ; Arginase/genetics ; B7-1 Antigen/immunology ; B7-H1 Antigen ; CD11b Antigen/analysis ; CD8-Positive T-Lymphocytes/immunology ; CTLA-4 Antigen ; Carcinoma/enzymology ; Carcinoma/immunology ; Carcinoma/pathology ; Cell Line, Tumor/immunology ; Cell Line, Tumor/transplantation ; Enzyme Induction ; Female ; Male ; Membrane Glycoproteins/immunology ; Mice ; Mice, Inbred C57BL ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/physiology ; Ovarian Neoplasms/enzymology ; Ovarian Neoplasms/immunology ; Ovarian Neoplasms/pathology ; Peptides/immunology ; Programmed Cell Death 1 Receptor ; RNA Interference ; RNA, Small Interfering/genetics ; RNA, Small Interfering/physiology ; Receptors, Chemokine/analysis ; Specific Pathogen-Free Organisms |
| Chemical Substances | 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 (EC 3.5.3.1) |
| Language | English |
| Publishing date | 2008-10-01 |
| Publishing country | Germany |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 195342-4 |
| ISSN | 1432-0851 ; 0340-7004 |
| ISSN (online) | 1432-0851 |
| ISSN | 0340-7004 |
| DOI | 10.1007/s00262-008-0591-5 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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