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糖基化B7-H5/VISTA免疫检查点蛋白在转移性透明细胞肾细胞癌中的功能作用

A functional role for glycosylated B7-H5/VISTA immune checkpoint protein in metastatic clear cell renal cell carcinoma.

作者信息

Emaldi Maite, Alamillo-Maeso Paula, Rey-Iborra Esther, Mosteiro Lorena, Lecumberri David, Pulido Rafael, López José I, Nunes-Xavier Caroline E

机构信息

Department of Cancer, Biobizkaia Health Research Institute, 48903 Barakaldo, Spain.

CIBERER, ISCIII, 28029 Madrid, Spain.

出版信息

iScience. 2024 Jul 25;27(9):110587. doi: 10.1016/j.isci.2024.110587. eCollection 2024 Sep 20.

DOI:10.1016/j.isci.2024.110587
PMID:39262813
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11388181/
Abstract

Increased expression of the B7 family of immune checkpoint proteins hinders tumor elimination by the immune system. Expression levels of the B7-H5 protein were found to be upregulated in clear cell renal cell carcinomas (ccRCC). We here report the molecular, functional, and clinical characterization of B7-H5 from renal cancer cells and metastatic ccRCC tumors. B7-H5 was highly glycosylated and mainly expressed in the cell membrane. Mutagenic studies on B7-H5 identified the residues targeted by N-glycosylation and revealed an impact of B7-H5 glycosylation on protein expression levels and localization. B7-H5 knockdown decreased the cell proliferation and viability of renal cancer cells. We analyzed B7-H5 expression on tumor cells and tumor-infiltrated leukocytes (TILs) in samples from metastatic ccRCC patients and found that B7-H5 expression on TILs correlated with syncronous metastases and poor outcomes. These results provide insights into the molecular properties and clinical impact of B7-H5 and support B7-H5 as a new immunotherapeutic target in metastatic ccRCC.

摘要

免疫检查点蛋白B7家族的表达增加会阻碍免疫系统对肿瘤的清除。研究发现，在透明细胞肾细胞癌（ccRCC）中，B7-H5蛋白的表达水平上调。我们在此报告了来自肾癌细胞和转移性ccRCC肿瘤的B7-H5的分子、功能和临床特征。B7-H5高度糖基化，主要表达于细胞膜。对B7-H5的诱变研究确定了N-糖基化靶向的残基，并揭示了B7-H5糖基化对蛋白质表达水平和定位的影响。敲低B7-H5可降低肾癌细胞的增殖和活力。我们分析了转移性ccRCC患者样本中肿瘤细胞和肿瘤浸润白细胞（TIL）上的B7-H5表达，发现TIL上的B7-H5表达与同步转移和不良预后相关。这些结果为B7-H5的分子特性和临床影响提供了见解，并支持将B7-H5作为转移性ccRCC的新免疫治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/f2434ff02769/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/6c04332043ac/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/b049683bab2d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/5d61a2161e5a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/9d05bea59e8d/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/ec217890a51a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/4ebf6cb05565/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/f2434ff02769/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/6c04332043ac/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/b049683bab2d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/5d61a2161e5a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/9d05bea59e8d/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/ec217890a51a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/4ebf6cb05565/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/62ad/11388181/f2434ff02769/gr6.jpg

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Impact of B7-H3 expression on metastasis, immune exhaustion and JAK/STAT and PI3K/AKT pathways in clear cell renal cell carcinoma.B7-H3表达对透明细胞肾细胞癌转移、免疫耗竭及JAK/STAT和PI3K/AKT信号通路的影响
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