Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
Mod Pathol. 2020 Feb;33(2):303-311. doi: 10.1038/s41379-019-0364-z. Epub 2019 Sep 19.
V-domain Ig-containing suppressor of T-cell activation (VISTA) is an immune checkpoint gene that inhibits anti-tumor immune responses. Since most malignant pleural mesotheliomas do not respond to anti-programmed cell death(-ligand)1 (PD-(L)1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) therapy and given the recent finding of The Cancer Genome Atlas Study that pleural mesothelioma displays the highest expression of VISTA among all cancers studied, we examined VISTA expression in a large pleural mesothelioma cohort. VISTA and PD-L1 immunohistochemistry were performed on tissue microarray of immunotherapy-naive pleural mesotheliomas (254 epithelioid, 24 biphasic and 41 sarcomatoid) and ten whole-tissue sections of benign pleura (VISTA only). Percentages of tumor and inflammatory cells with positive staining were assessed. Optimal prognostic cutoff percentages were determined using maximally selected rank statistics. Overall survival was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis. All benign mesothelium expressed VISTA. Eighty-five percent of 319 and 38% of 304 mesotheliomas expressed VISTA and PD-L1 (88% and 33% of epithelioid, 90% and 43% of biphasic, and 42% and 75% of sarcomatoid), respectively. Median VISTA score was significantly higher in epithelioid (50%) (vs. biphasic [20%] and sarcomatoid [0]) (p < 0.001), while median PD-L1 score was significantly higher in sarcomatoid tumors (20%) (vs. biphasic and epithelioid [both 0%]) (p < 0.001). VISTA and PD-L1 were expressed in inflammatory cells in 94% (n = 317) and 24% (n = 303) of mesothelioma, respectively. Optimal prognostic cutoffs for VISTA and PD-L1 were 40% and 30%, respectively. On multivariable analysis, VISTA and PD-L1 expression in mesothelioma were associated with better and worse overall survival (p = 0.001 and p = 0.002), respectively, independent of histology. In a large cohort of mesothelioma, we report frequent expression of VISTA and infrequent expression of PD-L1 with favorable and unfavorable survival correlations, respectively. These findings may explain poor responses to anti-PD-(L)1 immunotherapy and suggest VISTA as a potential novel target in pleural mesothelioma.
V-结构域免疫球蛋白抑制 T 细胞激活因子（VISTA）是一种免疫检查点基因，可抑制抗肿瘤免疫反应。由于大多数恶性胸膜间皮瘤对抗程序性细胞死亡（-配体）1（PD-（L）1）/细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）治疗无反应，并且最近的癌症基因组图谱研究发现胸膜间皮瘤在所有研究的癌症中显示出最高的 VISTA 表达，因此我们在大型胸膜间皮瘤队列中检查了 VISTA 表达。对免疫治疗初治性胸膜间皮瘤（254 例上皮样、24 例双相和 41 例肉瘤样）的组织微阵列和 10 个良性胸膜的全组织切片（仅 VISTA）进行了 VISTA 和 PD-L1 免疫组织化学染色。评估了阳性染色的肿瘤和炎症细胞的百分比。使用最大选择秩统计确定最佳预后截断百分比。使用 Kaplan-Meier 方法和 Cox 比例风险分析评估总生存率。所有良性间皮均表达 VISTA。319 例中的 85%和 304 例中的 38%表达 VISTA 和 PD-L1（上皮样分别为 88%和 33%，双相为 90%和 43%，肉瘤样为 42%和 75%）。上皮样肿瘤的中位 VISTA 评分明显更高（50%）（与双相[20%]和肉瘤样[0%]相比）（p<0.001），而肉瘤样肿瘤的中位 PD-L1 评分明显更高（20%）（与双相和上皮样[均为 0%]相比）（p<0.001）。VISTA 和 PD-L1 在 94%（n=317）和 24%（n=303）的间皮瘤中分别在炎症细胞中表达。VISTA 和 PD-L1 的最佳预后截断值分别为 40%和 30%。多变量分析显示，间皮瘤中 VISTA 和 PD-L1 的表达与更好和更差的总生存率相关（p=0.001 和 p=0.002），独立于组织学。在大型间皮瘤队列中，我们报告了 VISTA 的频繁表达和 PD-L1 的不频繁表达，分别与有利和不利的生存相关。这些发现可能解释了对抗 PD-（L）1 免疫治疗的反应不佳，并提示 VISTA 可能是胸膜间皮瘤的一个潜在新靶点。
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