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Alterations in the immune response of patients with cancer have been described for several decades. Tumor associated suppressor myeloid cells (TAMC) produce high amounts of arginase I, which depletes L-Arginine in the microenvironment, inhibits CD3ζ expression and blocks T cell proliferation. However, the mechanisms of arginase induction I in TAMC are poorly understood. The aim of this study was to characterize the mechanisms of induction of arginase I in 3LL tumors. The results show that arginase I induction in the TAMC is independent of cytokine produced by T cells, as shown by a similar arginase I expression in tumor bearing SCID mice and wild type C57BL/6. In contrast, TAMC co-cultured with 3LL cells or 3LL supernatants maintained the expression of arginase I. 3LL cells constitutively express COX-1 and COX-2 and produce high levels of PGE2, which can induce arginase I in macrophages. Blocking of PGE2 partially prevented arginase I induction. Furthermore, inhibition of COX-2, but not COX-1, using pharmacological agents or siRNA probes completely blocked arginase I induction by 3LL cells both in vitro and in tumor bearing mice. Use of PGE2 analogs suggested that signaling through EP4 receptor plays an important role on the arginase I induction. Altogether the data suggest that the production of prostanoids, including PGE2, by tumor cells are important in the arginase I induction in tumors.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]