Renal cell tumors convert natural killer cells to a proangiogenic phenotype

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 nonclassical 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 dNKlike phenotype in RCC tumors. These characteristics are conceivably beneficial for placentation, but likely exploited to support early tumor growth and promote metastasis.

Intratumor Regulatory Noncytotoxic NK Cells in Patients with Hepatocellular Carcinoma

“…Moreover, these NK cells are phenotypically and functionally similar to NK cells infiltrating decidua that are shifted toward non-cytotoxic regulatory functions [ 57 , 65 ] and may play a pro-oncogenic role. It has been shown that NK cells may promote tumor growth and vascularization of trophoblast choriocarcinomas [ 39 ] in non–small-cell lung cancer (NSCLC) and renal cell carcinoma, where NK cells can acquire the decidual-like CD56 bright CD16- phenotype related to proangiogenic functions [ 66 , 67 ]. Our results are in favor of a similar role in HCC.…”

Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

“…There is mounting evidence that NK cells infiltrate various tumors. For instance, NK cells were shown to infiltrate renal cell carcinoma [ 178 , 179 , 180 , 181 , 182 ], melanoma [ 183 , 184 ], breast cancer [ 185 , 186 , 187 , 188 ], hepatocellular carcinoma [ 189 , 190 , 191 ], lung cancer [ 192 , 193 ], prostate cancer [ 194 ], bladder cancer [ 195 ] and rectal cancer [ 196 ]. Although many studies show the presence of intratumoral CD56+ NK cells, studies have also found that intratumoral NK cell infiltration is very low or nonexistent in glioblastoma [ 197 ], colorectal cancer (CRC) [ 198 ], melanoma [ 199 , 200 ], renal cell carcinoma [ 157 ], hepatocellular carcinoma [ 200 ] and breast cancer [ 200 ].…”

Angiogenic Properties of NK Cells in Cancer and Other Angiogenesis-Dependent Diseases

“…There is a unique subset of decidual NK (dNK) cells known to participate in vascularization during embryonic and placental development [ 7 ]. Recently, a similar nurturing activity of NK cells has been described under pathological conditions, predominantly in different types of cancer, which indicates the relevance of NK cells in the development of ADDs [ 8 , 9 , 10 , 11 , 12 , 13 ]. A better understanding of the mechanisms in which NK cells regulate angiogenesis and its disorders may be of therapeutic significance.…”

“…TGF-β is the most immunosuppressive cytokine in the TME and its increased expression has been found in many types of tumors [ 94 ]. Elevated levels of this cytokine were also found in the plasma of patients with lung cancer [ 95 ], colorectal cancer (CRC) [ 96 ], and renal cell carcinoma (RCC) [ 12 ]. Various tumor cells, including cancer cells, stromal cells, immune cells, and myeloid-derived suppressor cells (MDSCs) are responsible for the excessive TGF-β production in cancer patients [ 97 ].…”