Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma.
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.
Ochoa
Augusto C
AC
Stanley 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
Zea
Arnold H
AH
Hernandez
Claudia
C
Rodriguez
Paulo C
PC
D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000378:metabolism; D039481:CD11b Antigen / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011453:Prostaglandins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
D039481:CD11b Antigen; D018950:Lipopolysaccharide Receptors; D011453:Prostaglandins; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D001119:Arginase; D015232:Dinoprostone