Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago 683-8503, Japan; Clinical Pathology Department, Medical Faculty of Sebelas Maret University, Surakarta 57126, Indonesia.
Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago 683-8503, Japan; Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
Hum Pathol. 2019 Feb;84:52-61. doi: 10.1016/j.humpath.2018.09.003. Epub 2018 Sep 18.
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer, with approximately 80% of cases related to Merkel cell polyomavirus (MCPyV). Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are the key rate-limiting enzymes of the tryptophan-to-kynurenine metabolic pathway. With aryl hydrocarbon receptor (AhR), an intracellular transcription factor, they play a role in escaping the immunosurveillance process in several cancers. IDO1/TDO2/AhR expression associated with the MCPyV status and prognosis in MCC was investigated. Samples included 24 MCPyV-positive MCCs, 12 MCPyV-negative MCCs with squamous cell carcinoma, and 7 MCPyV-negative pure MCCs. They were stained immunohistochemically with IDO1, TDO2, and AhR antibodies and analyzed. Higher IDO1 expression in MCC tumor cells was found in MCPyV-negative than in MCPyV-positive MCC (P < .001). The tumor microenvironment (TME) in MCPyV-negative MCC expressed higher TDO2 than in MCPyV-positive MCC (P < .001). Kaplan-Meier and log-rank tests showed that MCC with lower IDO1 expression in tumor cells and with lower TDO2 and AhR expressions in TME had better overall survival than otherwise (P = .043, .008, and .035, respectively); lower TDO2 expression in TME was also associated with longer disease-specific survival (P = .016). This suggests that IDO1, TDO2, and AhR express differentially in tumor cells or TME and play different roles in tumorigenesis between MCPyV-positive and MCPyV-negative MCC that may affect the MCC biology. Evaluating IDO1/TDO2/AhR expression is important for selecting the most likely patients with MCC for immunotherapies targeting the IDO1/TDO2-AhR pathway.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种罕见的侵袭性神经内分泌皮肤癌，约 80%的病例与默克尔细胞多瘤病毒（Merkel cell polyomavirus，MCPyV）有关。吲哚胺 2,3-双加氧酶 1（indoleamine 2,3-dioxygenase 1，IDO1）和色氨酸 2,3-双加氧酶 2（tryptophan 2,3-dioxygenase 2，TDO2）是色氨酸到犬尿氨酸代谢途径的关键限速酶。与细胞内转录因子芳烃受体（aryl hydrocarbon receptor，AhR）一起，它们在几种癌症的免疫逃避过程中发挥作用。本研究旨在探讨 IDO1/TDO2/AhR 的表达与 MCC 中的 MCPyV 状态和预后的关系。样本包括 24 例 MCPyV 阳性 MCC、12 例 MCPyV 阴性伴鳞状细胞癌 MCC 和 7 例 MCPyV 阴性单纯 MCC。用 IDO1、TDO2 和 AhR 抗体进行免疫组织化学染色，并进行分析。结果显示，MCPyV 阴性 MCC 肿瘤细胞中的 IDO1 表达高于 MCPyV 阳性 MCC（P <.001）。MCPyV 阴性 MCC 的肿瘤微环境（tumor microenvironment，TME）中 TDO2 的表达高于 MCPyV 阳性 MCC（P <.001）。Kaplan-Meier 和对数秩检验显示，肿瘤细胞中 IDO1 表达较低、TME 中 TDO2 和 AhR 表达较低的 MCC 患者总生存率较高（P =.043、.008 和.035）；TME 中 TDO2 表达较低与疾病特异性生存率延长相关（P =.016）。这表明 IDO1、TDO2 和 AhR 在肿瘤细胞或 TME 中的表达不同，在 MCPyV 阳性和 MCPyV 阴性 MCC 中的肿瘤发生中发挥不同的作用，可能影响 MCC 的生物学特性。评估 IDO1/TDO2/AhR 的表达对于选择最有可能接受 IDO1/TDO2-AhR 通路免疫治疗的 MCC 患者非常重要。
