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Innovations and Challenges in Renal Cancer |
Authors' Affiliations: Stanley S. Scott Cancer Center and Department of Pediatrics, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana
Requests for reprints: Augusto C. Ochoa, Stanley S. Scott Cancer Center and Department of Pediatrics, Louisiana State University Health Sciences Center and Louisiana Cancer Research Consortium, 533 Bolivar Street, New Orleans, LA 70112. E-mail: aochoa{at}lsuhsc.edu.
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-
production and T-cell proliferation. Preliminary data suggest that prostaglandin E2 produced by the tumor induces arginase I expression in MDSC. Therefore, blocking MDSC activity may enhance the therapeutic efficacy of immunotherapy in RCC.
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