Abstract
Natural killer (NK) cells are classically associated with immune surveillance and destruction of tumor cells. Inconsistent with this function, NK cells are found in advanced human tumors including renal cell carcinoma (RCC). NK cells with non-classical phenotypes (CD56+CD16dim/neg; termed decidua NK (dNK) cells) accumulate at the maternal-fetal interface during embryo implantation. These dNK cells are poorly cytotoxic, proangiogenic, and facilitate placenta development. As similarities between embryo implantation and tumor growth exist, we tested the hypothesis that an analogous shift in NK cell phenotype and function occurs in RCC tumors. Our results show that peripheral NK (pNK) cells of RCC patients were uniformly CD56+CD16bright, but lacked full cytotoxic ability. By comparison, RCC tumor-infiltrated NK (TiNK) cells were significantly enriched for CD56+CD16dim-neg cells, a phenotype of dNK cells. Gene expression analysis revealed that angiogenic and inflammatory genes were significantly increased for RCC TiNK versus RCC pNK populations, with enrichment of genes in the hypoxia inducible factor (HIF) 1α pathway. Consistent with this finding, NK cells cultured under hypoxia demonstrated limited cytotoxicity capacity, but augmented production of vascular endothelial growth factor (VEGF). Finally, comparison of gene expression data for RCC TiNK and dNK cells revealed a shared transcriptional signature of genes with known roles in angiogenesis and immunosuppression. These studies confirm conversion of pNK cells to a dNK-like phenotype in RCC tumors. These characteristics are conceivably beneficial for placentation, but likely exploited to support early tumor growth and promote metastasis.
Highlights
In humans, natural killer (NK) cells make up 5–20% of the nucleated cells in the peripheral blood, and are identified as CD3neg lymphocytes that express CD56 with or without CD16
We hypothesized that NK cells of renal cell carcinoma (RCC) patients were phenotypically and functionally altered within the circulation and/or tumor environment resulting in impaired tumor immunity
NK cells were isolated from peripheral blood mononuclear cells (PBMC) by negative selection using a cocktail of antibody-magnetic microbeads
Summary
Natural killer (NK) cells make up 5–20% of the nucleated cells in the peripheral blood, and are identified as CD3neg lymphocytes that express CD56 with or without CD16. These two subtypes of NK cells demonstrate distinct differences in phenotype and function. A small percentage (5–10%) of pNK cells are CD56+CD16dim/neg with little cytotoxic function and enhanced proinflammatory cytokine production, including gamma interferon (IFNγ), tumor necrosis factor alpha (TNFα), and granulocyte macrophage-colony stimulating www.oncotarget.com factor (GM-CSF) [1]. Tumor-infiltrated NK (TiNK) cells have impaired tumor cytotoxicity and increased proinflammatory cytokine production [2, 3]. Less is known regarding the proangiogenic properties of TiNK cells or the mechanisms driving functional conversion [4]
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