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Proangiogenic neutrophilic-myeloid-derived suppressor cells emerge via two parallel pathways in renal cell carcinoma and melanoma
© Ko et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Targeted therapy including anti-angiogenic therapy, kinase inhibitors, and immunotherapy dominate cancer drug development in renal cell carcinoma (RCC) and malignant melanoma (MM), where traditional methodologies have failed. Myeloid-derived suppressor cells (MDSC) may represent a mode of resistance to such treatments and require investigation in human patients. Here we explore the relationship between conventional neutrophils and neutrophilic-MDSC (nMDSC) in RCC and MM. We show that T-cell suppressive nMDSC consist of hypodense CD11b+CD15+CD14- immature CD16- myelocytes/metamyelocytes and mature CD16+ neutrophils co-precipitating with peripheral blood mononuclear cells (PBMCs) in patient blood (n=22) and tumors (n=16). Such cells were not significantly present in healthy blood donors (n=5). In parallel, conventional neutrophils co-precipitating with red blood cells (RBCs) were found to be uniquely immunosuppressive when isolated from RCC or MM patients (n=8), but not when isolated from healthy blood donors (n=5)(p<0.05). Both hypodense n-MDSC as well as conventional neutrophils from cancer patients expressed increased levels of pro-angiogenic molecules (n=4) and enhanced tumor-associated angiogenesis of RCC and MM xenografts in nude mice (p<.0001). This functional shift in mature neutrophils was modeled in vitro upon exposure of healthy donor derived neutrophils to tumor cell conditioned medium; and, was associated with an increase in neutrophil production of immunosuppressive arginase and reactive oxygen species, as well as an increase in proangiogenic molecule expression and in vivo angiogenic activity (n=3, p<.0001). The data support a role for nMDSC that are both T-cell suppressive and pro-angiogenic in RCC and MM cancer patients. Furthermore, our experiments suggest that n-MDSC arise via the parallel premature egress of bone marrow myeloid precursors as well as a functional switch in conventional neutrophil activity in cancer patients. Such activity is at least in part mediated via soluble tumor-derived factors which may circulate in patient blood. Ancillary strategies targeting myeloid cells may be an important part of future clinical trials to enhance the potency of targeted therapy.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.