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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / genetics
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Antigens, CD / physiology*
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Antigens, Surface / analysis
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Antigens, Surface / genetics
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Antigens, Surface / physiology*
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Apoptosis Regulatory Proteins / analysis
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology*
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Arginase / biosynthesis*
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Arginase / genetics
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B7-1 Antigen / immunology
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B7-H1 Antigen
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CD11b Antigen / analysis
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CD8-Positive T-Lymphocytes / immunology*
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CTLA-4 Antigen
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Carcinoma / enzymology*
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Carcinoma / immunology
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Carcinoma / pathology
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Cell Line, Tumor / immunology
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Cell Line, Tumor / transplantation
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Enzyme Induction
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Female
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Male
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Membrane Glycoproteins / immunology
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Mice
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Mice, Inbred C57BL
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Ovarian Neoplasms / enzymology*
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Ovarian Neoplasms / immunology
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Ovarian Neoplasms / pathology
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Peptides / immunology
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Programmed Cell Death 1 Receptor
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RNA Interference
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RNA, Small Interfering / genetics
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RNA, Small Interfering / physiology
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Receptors, Chemokine / analysis
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Specific Pathogen-Free Organisms
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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CD11b Antigen
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CTLA-4 Antigen
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CTLA4 protein, human
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Cd274 protein, mouse
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Ctla4 protein, mouse
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Gr-1 protein, mouse
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Membrane Glycoproteins
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Neoplasm Proteins
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Pdcd1 protein, mouse
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Peptides
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Programmed Cell Death 1 Receptor
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RNA, Small Interfering
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Receptors, Chemokine
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Arginase