Renal cell tumors convert natural killer cells to a proangiogenic phenotype

Abstract

// Yue Guan 1 , Christopher B. Chambers 1 , Taylor Tabatabai 1 , Ha Hatley 1 , Kristin R. Delfino 3 , Kathy Robinson 4 , 5 , Shaheen R. Alanee 2 , 5 , Sophia Ran 1 , 5 , Donald S. Torry 1 , 5 and Andrew Wilber 1 , 5 1 Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA 2 Department of Surgery, Division of Urology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA 3 Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL 62702, USA 4 Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA 5 Simmons Cancer Institute, Springfield, IL 62702, USA Correspondence to: Andrew Wilber, email: [email protected] Keywords: kidney cancer; innate immunity; natural killer cells; immunosuppression; angiogenesis Received: March 27, 2020     Accepted: June 05, 2020     Published: June 30, 2020 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 + CD16 dim/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 + CD16 bright , but lacked full cytotoxic ability. By comparison, RCC tumor-infiltrated NK (TiNK) cells were significantly enriched for CD56 + CD16 dim-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.

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