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

Cancer Immunol Immunother. 2009 May;58(5):687-97. doi: 10.1007/s00262-008-0591-5. Epub 2008 Oct 1.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • 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