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[Cancer Research 64, 5839-5849, August 15, 2004]
© 2004 American Association for Cancer Research

Immunology

Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses

Paulo C. Rodriguez1, David G. Quiceno1, Jovanny Zabaleta2, Blair Ortiz1, Arnold H. Zea1, Maria B. Piazuelo2, Alberto Delgado2, Pelayo Correa2, Jason Brayer4, Eduardo M. Sotomayor4, Scott Antonia4, Juan B. Ochoa5 and Augusto C. Ochoa1,3

1 Tumor Immunology Program, Stanley S. Scott Cancer Center, and 2 Departments of Pathology and 3 Pediatrics, Louisiana State University, Health Sciences Center, New Orleans, Louisiana; 4 H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida; and 5 Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

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 CD3{zeta} 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 CD3{zeta} 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 CD3{zeta} 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.




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