Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

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 À myeloid cells and resulted in significantly decreased serum levels of arginine and increased ornithine in patients. Depletion of MDSC restored IFN-g 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. Immunotherapy with cytokines, such as interleukin-2 (IL-2),has become a standard of care for patients with renal cell carcinoma (RCC). However, only 20% to 30% of patients have a partial or complete response (1), which is significantly lower than the therapeutic efficacy suggested by animal models. One possible explanation is that tumor-induced tolerance diminishes the potential therapeutic effect of T cells, the principal effector cells in most forms of immunotherapy. Over the last decade, several mechanisms by which tumors escape the immune response have been described. These can be divided into three major groups: alterations in antigen expression in tumor cells to make them less detectable, the active suppression of dendritic and T-cell function by inhibitory molecules or factors produced by tumors, and the induction of cells that can suppress the immune response, including myeloid-derived suppressor cells (MDSC) and regulatory T cells. We have focused our work on characterizing MDSC and the mechanisms by which they cause T-cell dysfunction in cancer.

Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor

“…Another immune function that could mediate the effects of surgery is myeloid-derived suppressor cells (MDSCs) (expressing CD11b/Gr-1 markers) that were shown to invade the spleen following traumatic stress and cause T cell dysfunction by an arginase-mediated mechanism (45). Indeed, in renal cell carcinoma patients, PGE 2 produced by the tumor was suggested to induce arginase-I expression in MDSCs, and depletion of MDSCs restored IFN-g production and T cell proliferation (46).…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…In particular, the inhibition of COX-2 activity and PGE2 production reported to reduce the MDSC trafficking mediated by chemokines CXCR4/CXCL12 and CXCR1-CXCR2/CXCL8 [83] has been also shown to impair the MDSC-mediated immunosuppression through the down-regulation of ROS and NO production [117,118] or ARG-1 expression in these cells [119].…”

Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes

“…As the activity of indoleamine 2,3-dioxygenase (Munn et al, 2002) or arginase (Ochoa et al, 2007) can decrease the ability of DC to stimulate T cells, we tested the activity of both enzymes in DC differentiated under the effects of VEGF, without finding evidence of increased activity even in the presence of pharmacological antagonists (Supplementary Figure 1). The decrease in MLR stimulating activity caused by RCC culture supernatants could not be restored by bevacizumab, sorafenib or sunitinib, delivered either as single agent or in combination ( Figures 1B and 2B).…”