Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma

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Abstract

Myeloid suppressor cells (MSCs) producing high levels of arginase I block T cell function by depleting l-arginine in cancer, chronic infections, and trauma patients. In cancer, MSCs infiltrating tumors and in circulation are an important mechanism for tumor evasion and impair the therapeutic potential of cancer immunotherapies. However, the mechanisms that induce arginase I in MSCs in cancer are unknown. Using the 3LL mouse lung carcinoma, we aimed to characterize these mechanisms. Arginase I expression was independent of T cell–produced cytokines. Instead, tumor-derived soluble factors resistant to proteases induced and maintained arginase I expression in MSCs. 3LL tumor cells constitutively express cyclooxygenase (COX)-1 and COX-2 and produce high levels of PGE ₂. Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE ₂ receptor E-prostanoid 4 expressed in MSCs induced arginase I. Furthermore, blocking arginase I expression using COX-2 inhibitors elicited a lymphocyte-mediated antitumor response. These results demonstrate a new pathway of prostaglandin-induced immune dysfunction and provide a novel mechanism that can help explain the cancer prevention effects of COX-2 inhibitors. Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies.

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Most cited references 51

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Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism.

M. A. Mazzoni, Alberto Visintin, Paola Zanovello … (2002)

CD11b(+)Gr-1(+) myeloid suppressor cells (MSC) accumulate in lymphoid organs under conditions of intense immune stress where they inhibit T and B cell function. We recently described the generation of immortalized MSC lines that provide a homogeneous source of suppressor cells for dissecting the mechanism of suppression. In this study we show that the MSC lines potently block in vitro proliferation of T cells stimulated with either mitogen or antigenic peptide, with as few as 3% of MSC cells causing complete suppression. Inhibition of mitogenic and peptide-specific responses is not associated with a loss in IL-2 production or inability to up-modulate the early activation markers, CD69 and CD25, but results in direct impairment of the three IL-2R signaling pathways, as demonstrated by the lack of Janus kinase 3, STAT5, extracellular signal-regulated kinase, and Akt phosphorylation in response to IL-2. Suppression is mediated by and requires NO, which is secreted by MSC in response to signals from activated T cells, including IFN-gamma and a contact-dependent stimulus. Experiments with inducible NO synthase knockout mice demonstrated that the inhibition of T cell proliferation by CD11b(+)Gr-1(+) cells in the spleens of immunosuppressed mice is also dependent upon NO, indicating that the MSC lines accurately represent their normal counterparts. The distinctive capacity of MSC to generate suppressive signals when encountering activated T cells defines a specialized subset of myeloid cells that most likely serve a regulatory function during times of heightened immune activity.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Med

Title: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 3 October 2005

Volume: 202

Issue: 7

Pages: 931-939

Affiliations

[1 ]Tumor Immunology Program, Stanley S. Scott Cancer Center

[2 ]Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112

[3 ]Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

[4 ]Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261

Author notes

CORRESPONDENCE Augusto C. Ochoa: aochoa@ 123456lsuhsc.edu OR ochoaaugusto@ 123456yahoo.com

Article

Publisher ID: 20050715

DOI: 10.1084/jem.20050715

PMC ID: 2213169

PubMed ID: 16186186

SO-VID: 2e435690-cbc2-440d-b3b4-2e5c318c023b

History

Date received : 8 April 2005

Date accepted : 10 August 2005

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