Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4. Tumor specimens were obtained from patients from two separate cohorts: One from “Evita Pueblo” Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR. Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased. In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.

中文翻译：

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免疫检查点HLA-G / ILT4参与了透明细胞肾细胞癌中VEGF表达的调节。

透明细胞肾细胞癌（ccRCC）是最具侵略性的肾癌，其特征是早期淋巴结转移和预后不良。作为一线治疗，大多数靶向晚期ccRCC或转移性ccRCC的疗法都是基于给予贝伐单抗的血管内皮生长因子（VEGF）中和抗体的给药。尽管已证明有益处，但大多数患者仍未获得预期的结果。血管生成与免疫检查点之间可能存在复杂相互作用的可能性，使我们通过VEGF表达与免疫检查点HLA-G / ILT4一起评估肿瘤的血管生成。肿瘤标本是从两个不同的队列中获得的：一个是从Berazategui的“ Evita Pueblo”医院（布宜诺斯艾利斯，阿根廷），第二位包括在圣路易医院（法国巴黎）泌尿外科进行手术且确诊为ccRCC的患者。用针对HLA-G，VEGF-A，VEGF-C，D240，CD34，ILT4和Ca-IX的特异性抗体进行免疫组织化学。另外，通过半定量RT-PCR在源自ccRCC患者的细胞系中测量基因表达水平。我们的结果表明，ccRCC患者的高度血管化肿瘤表达高水平的VEGF和免疫检查点HLA-G。此外，ILT4是HLA-G受体之一，在肿瘤细胞周围的巨噬细胞上被检测到，这表明可能产生免疫耐受的微环境可能有助于肿瘤发生。值得注意的是 RT-qPCR分析为HLA-G / ILT4与VEGF家族之间的转录关系提供了第一个证据。即，在HLA-G或ILT4存在下，VEGF-A的水平降低，而VEGF-C的水平升高。为了寻找新的治疗分子并对抗与ccRCC患者生存率低相关的转移扩散，这些发现为共同靶向血管生成和免疫检查点HLA-G提供了理论依据。