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Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma
Augusto C Ochoa1, Arnold H Zea, Claudia Hernandez
1Stanley S. Scott Cancer Center and Department of Pediatrics, Louisiana State University Health Sciences Center, 533 Bolivar Street, New Orleans, LA 70112, USA. aochoa@lsuhsc.edu
Abstract:
Tumor-induced tolerance is a well-established phenomenon in cancer patients that can severely impair the therapeutic efficacy of immunotherapy. One mechanism leading to T-cell tolerance is the generation of myeloid-derived suppressor cells (MDSC) by soluble factors produced by the tumor. MDSC express CD11b(+) as a common marker but may vary in their stage of maturation, depending on the tumor factors being produced. Arginase production by MDSC depletes arginine from the tumor microenvironment and impairs T-cell signal transduction and function. We studied whether an increase in MDSC could explain the molecular alterations and dysfunction found in T cells of patients with renal cell carcinoma (RCC). Arginase activity in the peripheral blood mononuclear cells of 117 RCC patients was increased between 6- to 8-fold compared with normal controls. The increased arginase activity was limited to the CD11b(+)CD14(-) myeloid cells and resulted in significantly decreased serum levels of arginine and increased ornithine in patients. Depletion of MDSC restored IFN-gamma production and T-cell proliferation. Preliminary data suggest that prostaglandin E(2) produced by the tumor induces arginase I expression in MDSC. Therefore, blocking MDSC activity may enhance the therapeutic efficacy of immunotherapy in RCC.
Insights
Myeloid-derived suppressor cells (MDSC) increase arginase activity in renal cell carcinoma (RCC) patients, depleting arginine and impairing T-cell function. Blocking MDSC may improve immunotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Tumor-induced tolerance hinders immunotherapy efficacy in cancer patients.
- Myeloid-derived suppressor cells (MDSC) are key mediators of this tolerance.
- MDSC impair T-cell function by depleting arginine via arginase production.
Purpose of the Study:
- To investigate if increased MDSC explain T-cell dysfunction in renal cell carcinoma (RCC).
- To assess arginase activity and arginine levels in RCC patients.
- To explore the role of prostaglandin E2 in MDSC-induced arginase expression.
Main Methods:
- Measured arginase activity in peripheral blood mononuclear cells (PBMCs) from 117 RCC patients and controls.
- Quantified serum arginine and ornithine levels.
- Analyzed MDSC populations (CD11b(+)CD14(-)) and their arginase activity.
- Assessed the impact of MDSC depletion on T-cell proliferation and IFN-gamma production.
- Investigated prostaglandin E2's role in inducing arginase I in MDSC.
Main Results:
- RCC patients exhibited 6- to 8-fold increased arginase activity in PBMCs compared to controls.
- Elevated arginase activity was localized to CD11b(+)CD14(-) myeloid cells.
- Patients showed significantly decreased serum arginine and increased ornithine levels.
- Depletion of MDSC restored T-cell proliferation and IFN-gamma production.
- Preliminary data indicate prostaglandin E2 induces arginase I expression in MDSC.
Conclusions:
- Increased MDSC and their arginase activity contribute to T-cell dysfunction in RCC.
- Arginine depletion by MDSC impairs T-cell signaling and function in RCC patients.
- Targeting MDSC activity presents a potential strategy to enhance immunotherapy efficacy in RCC.
