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Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma
Paulo C Rodriguez1, Claudia P Hernandez, David Quiceno
1Tumor Immunology Program, Stanley S. Scott Cancer Center, New Orleans, LA, USA.
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 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.
Insights
Tumor cells induce myeloid suppressor cells (MSCs) to produce arginase I via prostaglandin E2 (PGE2), blocking anti-cancer immunity. Inhibiting cyclooxygenase-2 (COX-2) reverses this, enhancing anti-tumor responses.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Myeloid suppressor cells (MSCs) inhibit T cell function by depleting L-arginine, aiding tumor evasion and hindering cancer immunotherapy.
- The mechanisms inducing arginase I in MSCs within the tumor microenvironment are not fully understood.
Purpose of the Study:
- To investigate the mechanisms responsible for inducing arginase I expression in MSCs in the context of cancer.
- To explore the role of tumor-derived factors and prostaglandin E2 (PGE2) in this process.
Main Methods:
- Utilized the 3LL mouse lung carcinoma model.
- Assessed arginase I expression in MSCs in response to tumor-derived factors.
- Investigated the role of cyclooxygenase (COX)-1 and COX-2, and PGE2 signaling via the E-prostanoid 4 receptor.
- Employed genetic and pharmacological inhibition of COX-2.
Main Results:
- Tumor-derived soluble factors, not T cell cytokines, induced arginase I in MSCs.
- Cyclooxygenase-2 (COX-2), but not COX-1, and its product PGE2 were crucial for arginase I induction.
- Signaling through the PGE2 receptor E-prostanoid 4 mediated arginase I expression.
- Inhibition of COX-2 reduced arginase I and promoted lymphocyte-mediated anti-tumor responses.
Conclusions:
- Identified a novel pathway where tumor-derived PGE2 induces arginase I in MSCs, leading to immune suppression.
- Demonstrated that COX-2 inhibitors can restore anti-tumor immunity by blocking this pathway.
- Suggests that targeting arginase I or COX-2 may enhance cancer immunotherapy efficacy.
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