Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer.
Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-17-2542
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发表时间：
2018-04-01
期刊：
影响因子：
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通讯作者：
Schalper KA
中科院分区：
文献类型：
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作者：
Villarroel-Espindola F;Yu X;Datar I;Mani N;Sanmamed M;Velcheti V;Syrigos K;Toki M;Zhao H;Chen L;Herbst RS;Schalper KA
确定VISTA/PD-1H在人NSCLC中的定位表达模式和临床意义。使用多重定量免疫荧光（QIF），我们在来自以组织微阵列格式表示的3个独立群组的758个I-IV期NSCLC中进行VISTA、PD-1和PD-L1蛋白的定位测量。在细胞角蛋白+肿瘤上皮细胞、CD 3 + T细胞、CD 4 + T辅助细胞、CD 8+细胞毒性T细胞、CD 20 + B淋巴细胞和CD 68+肿瘤相关巨噬细胞中选择性测量靶点。我们确定了靶点、临床病理学/分子变量和生存率之间的相关性。还对来自TCGA的肺癌病例进行了基因组分析。在99%的NSCLC中检测到VISTA蛋白，具有主要的膜/细胞质染色模式。在肿瘤和基质细胞中的表达分别见于21%和98%的病例。VISTA水平与PD-L1、PD-1、CD 8 + T细胞和CD 68+巨噬细胞正相关。VISTA表达在T淋巴细胞中高于巨噬细胞;并且在细胞毒性T细胞中高于T辅助细胞。VISTA升高与肺腺癌中EGFR突变的缺乏和较低的突变负荷相关。肿瘤隔室中VISTA的存在预测了更长的5年生存期。VISTA经常在人NSCLC中表达，并显示与TIL增加、PD-1轴标志物、特异性基因组改变和结果相关。这些结果支持VISTA在人NSCLC中的免疫调节作用，并表明其作为治疗靶标的潜力。
Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human NSCLC. Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1 and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin+ tumor epithelial cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells, CD20+ B-lymphocytes and CD68+ tumor-associated macrophages. We determined the association between the targets, clinico-pathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA was also performed. VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8+ T-cells and CD68+ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T-cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival. VISTA is frequently expressed in human NSCLC and shows association with increased TILs, PD-1 axis markers, specific genomic alterations and outcome. These results support the immuno-modulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target.