Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan.
Department of Pathology and Laboratory Medicine, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan.
Int J Cancer. 2018 Aug 1;143(3):610-620. doi: 10.1002/ijc.31336. Epub 2018 Mar 5.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated lymphoepithelioma. The aim of this study was to characterize the homogeneity and distinctness of the T-cell repertoires within and between primary and metastatic NPCs. We used ultra-deep sequencing of the hypervariably rearranged antigen-binding CDR3 regions of T-cell receptor beta (TCR ) to comprehensively profile the T-cell repertoires in NPC patients receiving definitive chemoradiotherapy with long-term follow-up. We observed not only various spatially heterogeneous patient-specific TCR clone compositions that changed with time but also several commonly enriched TCR subclones that were constantly shared between primary NPCs in the head and neck regions, locally recurrent tumors after treatment and later-developed distant metastatic tumors in the liver, lung and bone. Comparison of the overlap frequency of the T-cell clonality between TCR repertoires enabled us to calculate the pairwise genetic distance between primary NPCs of different patients and different sites of metastatic or recurrent NPCs. The constructed NPC phylogeny clearly differentiated the low-risk patients without relapse from the high-risk patients with distant metastasis after chemoradiotherapy. In contrast to the rather low frequency of nonsilent somatic mutations in NPC cells, the degrees of similarity and divergence of NPC-infiltrating lymphocyte TCR repertoires among different patients showed prognostication. Moreover, the persistent presence of commonly NPC-shared in-frame TCR CDR3 gene sequences spatiotemporally identified in the NPC-infiltrating lymphocytes within varied EBV-positive NPCs and their metastases suggest the existence of frequently shared epitopes of neoantigens virally or nonvirally displayed on cancer cells, thereby providing opportunities for the development of precisely tumor-targeted immunotherapy for distant metastasis.
鼻咽癌（NPC）是一种与 Epstein-Barr 病毒（EBV）相关的淋巴上皮瘤。本研究旨在描述原发和转移 NPC 内及之间 T 细胞受体（TCR）库的同质性和独特性。我们使用 TCR 高变区抗原结合 CDR3 区域的超深度测序，全面分析了接受根治性放化疗并长期随访的 NPC 患者的 T 细胞库。我们不仅观察到了各种随时间变化的空间异质性的患者特异性 TCR 克隆组成，还观察到了几个经常富集的 TCR 亚克隆，这些亚克隆在头颈部的原发 NPC、治疗后局部复发性肿瘤以及后来发生的肝、肺和骨远处转移性肿瘤中始终存在。比较 TCR 库之间 T 细胞克隆性的重叠频率，使我们能够计算不同患者的原发 NPC 之间以及转移性或复发性 NPC 不同部位之间的 T 细胞遗传距离。构建的 NPC 系统发育树清楚地区分了放化疗后无复发的低危患者和远处转移的高危患者。与 NPC 细胞中非沉默性体细胞突变的相当低频率相比，不同患者之间 NPC 浸润淋巴细胞 TCR 库的相似性和差异性程度显示了预后。此外，在不同 EBV 阳性 NPC 及其转移灶中，在 NPC 浸润淋巴细胞中随时间和空间持续存在的常见 NPC 共享框架内 TCR CDR3 基因序列，提示存在经常共享的新抗原表位，这些表位可以通过病毒或非病毒方式在癌细胞上展示，从而为开发针对远处转移的精确肿瘤靶向免疫治疗提供了机会。
