Spatiotemporal homogeneity and distinctness of the T-cell receptor β-chain repertoires in Epstein-Barr virus-associated primary and metastatic nasopharyngeal carcinomas

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated lymphoepithelioma. The aim of the present 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_beta) 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_beta clone compositions that changed with time but also several commonly enriched TCR_beta 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_beta 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 non-silent somatic mutations in NPC cells, the degrees of similarity and divergence of NPC-infiltrating lymphocyte TCR_beta repertoires among different patients showed prognostication. Moreover, the persistent presence of commonly NPC-shared in-frame TCR_beta 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 non-virally displayed on cancer cells, thereby providing opportunities for the development of precisely tumor-targeted immunotherapy for distant metastasis. This article is protected by copyright. All rights reserved.

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