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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2009-05, Vol.58 (5), p.687-697
• Main Authors: Liu, Yu, Yu, Yinyan, Yang, Suguang, Zeng, Bin, Zhang, Zhuohan, Jiao, Guohui, Zhang, Yuan, Cai, Limin, Yang, Rongcun
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antigens, CD - genetics; Antigens, CD - physiology; Antigens, Surface - analysis; Antigens, Surface - genetics; Antigens, Surface - physiology; Antineoplastic agents; Apoptosis Regulatory Proteins - analysis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Arginase - biosynthesis; Arginase - genetics; Arginase I; Ascites; B7-1 Antigen - immunology; B7-H1 Antigen; Biological and medical sciences; Cancer Research; Carcinoma - enzymology; Carcinoma - immunology; Carcinoma - pathology; CD11b Antigen - analysis; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor - immunology; Cell Line, Tumor - transplantation; CTLA-4; CTLA-4 Antigen; Cytokines; Enzyme Induction; Female; Immunology; Immunotherapy; Lymphocytes; Male; Medical sciences; Medicine; Medicine & Public Health; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Myeloid derived suppressor cells; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Oncology; Original; Original Article; Ovarian cancer; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - immunology; Ovarian Neoplasms - pathology; PD-1; Peptides - immunology; Pharmacology. Drug treatments; Programmed Cell Death 1 Receptor; Receptors, Chemokine - analysis; RNA Interference; RNA, Small Interfering - genetics; RNA, Small Interfering - physiology; Specific Pathogen-Free Organisms; Spleen; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-008-0591-5

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 wet among MDSCs.