The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma
The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma
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DOI：
10.1186/s12885-020-07113-8
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发表时间：
2020-07-03
期刊：
影响因子：
3.8
通讯作者：
Tronik-Le Roux, Diana
中科院分区：
文献类型：
--
作者：
Garcia, Marcela;Palma, Maria Belen;Tronik-Le Roux, Diana
肾透明细胞癌是最具侵袭性的肾癌，具有早期淋巴结转移和预后不良的特点。大多数针对晚期或转移性肾细胞癌的治疗都是基于血管内皮生长因子(VEGF)中和抗体Bevacizumab的一线治疗。尽管已证实有好处，但对大多数患者来说，并没有获得预期的结果。血管生成和免疫检查点之间可能存在错综复杂的相互作用，这使得我们通过血管内皮生长因子的表达和免疫检查点HLA-G/ILT4来评估肿瘤血管生成。方法肿瘤标本来自两个不同的队列：一个来自来自贝拉扎特吉的“Evita Pueblo”医院(阿根廷布宜诺斯艾利斯)，另一个包括在圣路易斯医院(法国巴黎)的泌尿科手术并确诊为cccRCC的患者。用抗人白细胞抗原-G、血管内皮生长因子-A、血管内皮生长因子-C、D240、CD34、ILT4和钙-IX的特异性抗体进行免疫组织化学染色。此外，采用半定量RT-PCR法检测了肾细胞癌患者肿瘤细胞系中的基因表达水平。结果表明，肾细胞癌患者高血管密度的肿瘤表达高水平的血管内皮生长因子和免疫检查点HLAG。此外，在肿瘤细胞周围的巨噬细胞上检测到了人类白细胞抗原G受体之一的ILT4，这表明可能产生了有利于肿瘤发生的免疫耐受微环境。值得注意的是，RT-qPCR分析为人类白细胞抗原G/ILT4和血管内皮生长因子家族之间的转录关系提供了第一个证据。结论为了寻找新的治疗分子，对抗与肾细胞癌患者低生存率相关的转移转移，这些发现为共同靶向血管生成和免疫检查点提供了理论依据。
BackgroundClear 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.MethodsTumor 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.ResultsOur 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.ConclusionsIn 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.