Location of Repository

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

By Paulo C. Rodriguez, Claudia P. Hernandez, David Quiceno, Steven M. Dubinett, Jovanny Zabaleta, Juan B. Ochoa, Jill Gilbert and Augusto C. Ochoa


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 PGE2. Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE2 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

Topics: Article
Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2213169
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles



    1. (1998). Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4 T cells correlates with Th1/Th2 phenotype.
    2. Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L-arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res.
    3. (1982). Arginase as an inhibitory principle in liver plasma membranes arresting the growth of various mammalian cells in vitro.
    4. (2002). Arginase I induction in macrophages, triggered by Th2-type cytokines, supports the growth of intracellular Leishmania parasites. Parasite Immunol.
    5. (2005). Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity.
    6. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res.
    7. (1995). Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages.
    8. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res.
    9. (1990). Arginine and immune function.
    10. (2005). Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.
    11. (2000). Cancer statistics,
    12. (1997). Chemopreventive efficacies of aspirin and sulindac against lung tumorigenesis in A/J mice.
    13. (2001). Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production.
    14. (2002). Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res.
    15. (2002). Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions.
    16. (2002). Differential effect of FR122047, a selective cyclo-oxygenase-1 inhibitor, in rat chronic models of arthritis.
    17. (2004). Enhancer-mediated control of macrophage-specific arginase I expression.
    18. (2001). Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival.
    19. (2000). Host cyclooxygenase-2 modulates carcinoma growth.
    20. (2003). IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice.
    21. (1998). Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res.
    22. (2000). Indomethacin inhibits the accumulation of tumor cells in mouse lungs and subsequent growth of lung metastases.
    23. (1997). Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.
    24. (1994). International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes.
    25. Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res.
    26. (2003). L-arginine consumption by macrophages modulates the expression of CD3zeta chain in T lymphocytes.
    27. (2002). Lung cancer–time to move on from chemotherapy.
    28. (2001). Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res.
    29. Mechanism of immune dysfunction in cancer mediated by immature Gr-1 myeloid cells.
    30. (2000). Meloxicam inhibits the growth of non-small cell lung cancer. Anticancer Res.
    31. (2004). Multifaceted roles of cyclooxygenase-2 in lung cancer. Drug Resist.
    32. (2002). Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism.
    33. (2003). Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells.
    34. (2005). Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.
    35. (2000). NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway.
    36. (2001). Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44.
    37. (1998). Non-small cell lung cancer cyclooxygenase-2-dependent regulation of cytokine balance in lymphocytes and macrophages: up-regulation of interleukin 10 and down-regulation of interleukin 12 production.
    38. (2000). Non-small-cell lung cancer– stalemate or progress?
    39. ornithine, as markers in human non-small cell lung carcinoma.
    40. (1982). Peritoneal adherent cell inhibit the generation of cytotoxic T lymphocytes with prostaglandin-mediated system.
    41. (1985). Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression.
    42. (1999). Prostaglandin E2 as a modulator of lymphocyte mediated inflammatory and humoral responses.
    43. (2003). Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases.
    44. (1999). Prostanoid receptors: structures, properties, and functions.
    45. (2004). Recent advances in arginine metabolism.
    46. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines.
    47. (2005). Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease.
    48. (2000). Regulation of prostaglandin E2 biosynthesis by inducible membraneassociated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2.
    49. (2000). Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis.
    50. (2005). STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion.
    51. (2003). Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell.
    52. (1999). Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells.
    53. (2001). The inhibition of arginase by N(omega)-hydroxy-l-arginine controls the growth of Leishmania inside macrophages.
    54. (1996). The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100.
    55. (1982). Tumor cell-triggered macrophage-mediated suppression of the T-cell cytotoxic response to tumorassociated antigens. II. Mechanisms for induction of suppression.
    56. (2004). Tumour cell growth in culture: dependence on arginine.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.