Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion.

By A. Zea, P. Rodriguez, M. Atkins, Claudia P. Hernández, S. Signoretti, J. Zabaleta, D. McDermott, D. Quiceno, A. Youmans, A. O'Neill and 2 more. Cancer Research, 2005

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Myeloid suppressor cells with high arginase activity are found in tumors and spleen of mice with colon and lung cancer. These cells, described as macrophages or immature dendritic cells, deplete arginine and impair T cell proliferation and cytokine production. Although arginase activity has been described in cancer patients, it is thought to originate from tumor cells metabolizing arginine to ornithine needed to sustain rapid cell proliferation. The goal of this study was to determine whether myeloid suppressor cells producing high arginase existed in renal cell carcinoma patients. Peripheral blood mononuclear cells from 123 patients with metastatic renal cell carcinoma, prior to treatment, were found to have a significantly increased arginase activity. These patients had a markedly decreased cytokine production and expressed low levels of T cell receptor CD3zeta chain. Cell separation studies showed that the increased arginase activity was limited to a specific subset of CD11b+, CD14-, CD15+ cells with a polymorphonuclear granulocyte morphology and markers, instead of macrophages or dendritic cells described in mouse models. Furthermore, these patients had low levels of arginine and high levels of ornithine in plasma. Depletion of the CD11b+, CD14- myeloid suppressor cells reestablished T cell proliferation and CD3zeta chain expression. These results showed, for the first time, the existence of suppressor myeloid cells producing arginase in human cancer patients. In addition, it supports the concept that blocking arginase may be an important step in the success of immunotherapy.

Subfields: Biotechnology, Immunology

View Paper: https://www.semanticscholar.org/paper/bb4313d2906301c9ba43ea2c32bebce16d800287

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HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment (2010, background): “In humans, MDSCs are generally defined as cells that express CD11b, the common myeloid marker CD33, but lack the expression of markers of mature myeloid and lymphoid cells and the MHC class II molecule HLA-DR (Almand et al., 2001; Zea et al., 2005; Diaz-Montero et al., 2009; Nagaraj et al., 2010).”
Mechanisms of immune evasion by tumors. (2006, background): “Immat ure mye loid ce lls ( Kusmar tsev and Gabril ovich, 2005; Young et al ., 2001 ) an d MSC ( Bronte et al. , 2000, 2003; Mazz oni et al. , 2002; Zea et al., 2005) represent a cadre of myeloid cell types, including tumor‐associated macrophages (TAM), that share the common feature of inhibiting…”
Myeloid-derived-suppressor cells as regulators of the immune system (2009, positive): “Accordingly, cyclooxygenase 2 inhibitors were found to downregulate the expression of arginase 1 by MDSCs, which improved antitumour T-cell responses and enhanced the therapeutic efficacy of immunotherap”
Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma (2005, background): “Furthermore, increased COX-2 expression and PGE2 production has been reported in human colon carcinomas, breast cancer (35), renal cell carcinoma (36), and lung carcinoma (37–39), which has led to the testing of COX-2 inhibitors as a means for cancer prevention.”
Infiltrating Blood-Derived Macrophages Are Vital Cells Playing an Anti-inflammatory Role in Recovery from Spinal Cord Injury in Mice (2009, background): “Notably, they share these features with the so-called myeloidderived suppressor cells (MDSC) [60,78–81], which were originally identified in the context of tumor immune escape mechanisms [78–85], and more recently it has been suggested that they have a role in non-CNS tissue repair [36,37] and in th”
Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells (2008, background): “In metastatic renal cell carcinoma, for example, a population of CD11b(1)CD14 CD15(1) cells with suppressive activity on T cells was described; these cells constitutively expressed ARG enzyme, which is involved in the immunoregulatory activity, but no MHC class II or costimulatory molecule (CD80, CD”
Mechanism regulating reactive oxygen species in tumor induced myeloid-derived suppressor cells (2009, background): “In humans, MDSC are identifiable as lineage (CD3, CD14, CD19, CD56)-negative, HLA-DR-negative, and CD33-positive (5) or CD11b CD14 CD33 cells (6).”