Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.

Abstract

T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3zeta chain and impairs T-cell responses. Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in the tumor microenvironment and could decrease CD3zeta expression and impair T-cell function. The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. Arginase I expression in the tumor was seen on day 7 after tumor injection. Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate L-Arginine (L-Arg) and deplete extracellular L-Arg in vitro. L-Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3zeta in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. The injection of the arginase inhibitor N-hydroxy-nor-L-Arg blocked growth of s.c. 3LL lung carcinoma in mice. High levels of arginase I were also found in tumor samples of patients with non-small cell carcinoma. Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.

• Authors: Paulo C Rodriguez, David G Quiceno, Jovanny Zabaleta, Blair Ortiz, Arnold H Zea, Maria B Piazuelo, Alberto Delgado, Pelayo Correa, Jason Brayer, Eduardo M Sotomayor, Scott Antonia, Juan B Ochoa, Augusto C Ochoa
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 16 Pg. 5839-49 (Aug 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15313928 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CD3 Complex
• CD3 antigen, zeta chain
• Epitopes, T-Lymphocyte
• Receptors, Antigen, T-Cell
• Arginase

Topics

• Amino Acid Sequence
• Animals
• Arginase (antagonists & inhibitors, biosynthesis, immunology)
• CD3 Complex (biosynthesis, immunology)
• Carcinoma, Lewis Lung (enzymology, immunology, pathology)
• Carcinoma, Non-Small-Cell Lung (enzymology, immunology, pathology)
• Cell Division (physiology)
• Epitopes, T-Lymphocyte (immunology)
• Female
• Humans
• Lung Neoplasms (enzymology, immunology, pathology)
• Lymphocyte Activation (immunology)
• Mice
• Molecular Sequence Data
• Myeloid Cells (enzymology, immunology)
• Receptors, Antigen, T-Cell (antagonists & inhibitors, biosynthesis)