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

By P. Rodriguez, Claudia P. Hernández, D. Quiceno, S. Dubinett, J. Zabaleta, J. Ochoa, J. Gilbert, Augusto Ochoa. Journal of Experimental Medicine, 2005

630 citations recorded by the source corpus.

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.

Subfields: Immunology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/492161da512dd3b685b432254870654c7fdfaf2c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Pharmacology

D. Gabrilovich

Citations in the corpus

Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives (2008, background): “silencing COX-2 in 3LL cells completely blocked their ability to induce arginase I in MDSC (132).”
Myeloid-derived suppressor cells (2017, background): “Inhibition of COX-2 downregulates the production of immunesuppressive PGE2, and nitroaspirin downregulates NO production (70, 71).”
Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function (2010, background): “Cox2 mRNA levels also directly correlated with the arg1 and nos2 transcript levels from tumor-infiltrating leukocytes, supporting the role of PGE2 as a regulator of arg1 and nos2 expression [65].”
Myeloid-derived-suppressor cells as regulators of the immune system (2009, neutral): “Recent data suggest that there is a close correlation between the availability of L -arginine and the regulation of T-cell proliferatio”
Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. (2007, background): “immunosurveillance by polarizing macrophages toward a tumorpromoting phenotype (58).”
Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. (2015, background): “Finally, inhibition of COX-2 decreased the production of immunosuppressive prostaglandin E2, and nitroaspirin has been shown to downregulate NO production (117, 118).”
Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer (2009, background): “Because COX-2 and PGE2 had been shown to increase arginase levels in mouse CD11b macrophages (89), the role of PG in MDSC induction was examined.”
Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. (2007, background): “Likewise, IL-6 (33, 36, 37), another proinflammatory mediator, and PGE2 (4, 38), a product of inflammation, induce MDSC accumulation.”
Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells (2008, background): “COX2 inhibition was described to lower ARG1 and NOS2 expression in secondary lymphoid organs, promoting tumor T-cell infiltration and resulting in reduced tumor multiplicity (75).”
Arginase: an emerging key player in the mammalian immune system (2009, background): “Alternatively, inhibition of cyclooxygenase-2 (expressed by murine 3LL lung carcinoma) and prevention of Prostaglandin E2-mediated arginase induction in MDSC led to effective tumour control (Rodriguez et al., 2005).”
Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells (2008, background): “We and others recently demonstrated that the inflammatory mediators IL-1 , IL-6, and PGE2 induce accumulation of myeloid-derived suppressor cells (MDSC) in tumorbearing individuals.”