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

PC Rodriguez, DG Quiceno, J Zabaleta, B Ortiz… - Cancer research, 2004 - AACR
PC Rodriguez, DG Quiceno, J Zabaleta, B Ortiz, AH Zea, MB Piazuelo, A Delgado, P Correa…
Cancer research, 2004AACR
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 CD3ζ chain and impairs T-cell responses.
Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in …
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 CD3ζ 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 CD3ζ 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 CD3ζ 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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