XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary
XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary
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DOI：
10.1038/s41388-020-1237-0
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发表时间：
2020-03-02
期刊：
影响因子：
8
通讯作者：
Enomoto, Takayuki
中科院分区：
文献类型：
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作者：
Tamura, Ryo;Yoshihara, Kosuke;Enomoto, Takayuki
由于卵巢成熟囊性畸胎瘤（MCT）的罕见性，其癌的分子特征仍不清楚。我们分析了2322例泛癌[1378例鳞状细胞癌（SCC），6例腺鳞癌（ASC）和938例腺癌（AC）]的RNA测序数据，其中包括6例MCT引起的癌（4例SCC，1例ASC和1例AC）。系统聚类和主成分分析表明，MCT引起的癌基因表达谱在不同组织学类型之间存在差异，MCT引起的SCC（MCT-SCC）基因表达谱与肺SCC基因表达谱明显相似。通过基于基因集富集分析的表皮相关通路活性，将1030例SCC分为两组：表皮特征高（头颈部、食管和皮肤）和低（宫颈、肺和MCT）。除了泛SCC转录组分析外，21个MCT-SCC独立样本中基于免疫组织化学的细胞角蛋白分析澄清了MCT-SCC主要表达CK 18，这表明MCT-SCC的起源是柱状上皮。随后，我们研究了MCT-SCC与不同SCC相比的差异表达基因，并确定XCL 1在MCT-SCC中特异性过表达。通过免疫组织化学分析，我们在13/24（54%）的MCT-SCC中的肿瘤细胞上发现了XCL 1表达，但在MCT中没有。XCL 1表达还与肿瘤浸润性CD 8阳性T细胞的数量和肿瘤细胞上的PD-L1表达显著相关。肿瘤细胞产生的XCL 1可诱导肿瘤微环境中的PD 1/PD-L1相互作用和CD 8阳性T细胞功能障碍。XCL 1表达可能是MCT恶性转化为SCC的一种新生物标志物，也可能是抗PD 1/PD-L1治疗反应的候选生物标志物。
Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.