免疫失调是鼻咽癌放射耐药的基础。

Haitao Wang, E. Yeo, J. Hwang, G. S. Tan, E. Ong, K. Low, Anusha Chimmiri, Wai Yee Woo, W. Nei, K. Lim, M. Tan, J. H. Loh, Constance Teo, H. Heah, G. Tay, J. Wee, N. Iyer, Ying Sun, J. Bei, M. Chua
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引用次数: 1

摘要

背景:放疗(RT)是鼻咽癌治疗的主要方式。然而,30%的患者在放疗后出现疾病复发。在这里,我们研究了与放射耐药(RR)鼻咽癌相关的分子和免疫谱。此外,我们研究了配对复发患者的异常分子途径,以发现支持放射耐药的新驱动因素。方法:我们前瞻性地招募了100名鼻咽癌患者,他们完成了最终的放疗/化疗;包括30例复发患者。采用200x全外显子组测序(WES)鉴定低频率(< 1%)的真体细胞核苷酸变异(snv)和拷贝数改变(CNAs)。使用监督和非监督统计方法对RNAseq的转录组谱进行查询,以确定与RR显著相关的异常通路。结果:以基因组改变百分比(PGA)为特征的基因组不稳定性在我们的队列中具有可比性。此外,我们没有观察到RR-和nr-NPC病例之间有任何共同或排他性的中枢神经系统病变。基于一系列免疫相关的特征,我们观察到与nr-NPC对照相比,RR-NPC具有“免疫冷”特征,其特征是CD8+ T细胞浸润和干扰素-γ反应的低表达。意料之中的是,与血管生成、缺氧和NOTCH信号通路相关的通路在RR-NPC队列中上调。有趣的是,我们观察到成对复发的免疫表型从“冷”逆转为效应T细胞浸润的富集。结论:在这里,我们展示了RR- npc的全面突变景观,揭示了免疫环境在调节RR中的潜在作用。肿瘤微环境在新生肿瘤和复发之间的纵向免疫失调可能是复发开始时的驱动或乘客事件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Immune dysregulation underpins radioresistance in nasopharyngeal carcinoma (NPC).
52 Background: Radiotherapy (RT) is a primary modality in the treatment of NPC. However, 30% of patients present with disease recurrence following RT of this radiosensitive tumor. Here, we investigated the molecular and immune profiles associated with radioresistant (RR) NPC. Additionally, we investigated for aberrant molecular pathways in paired recurrences of patients to uncover new drivers underpinning radioresistance. Methods: We prospectively recruited a cohort of 100 NPC patients who completed definitive RT/chemoRT; including 30 cases who were recruited at recurrence. Whole exome sequencing (WES) at 200x was performed to identify low frequencies ( < 1%) of true somatic nucleotide variants (SNVs) and copy number alterations (CNAs). Transcriptomic profiles from RNAseq were interrogated using supervised and unsupervised statistical approaches to determine aberrant pathways that were significantly associated with RR. Results: Genomic instabilityas characterized by percentage genome alteration (PGA) was comparable in our cohort. Additionally, we did not observe any common or exclusive CNAs between RR- and nr-NPC cases. Based on a constellation of immune-related signatures, we observed an “immune-cold” profile that is associated with RR-NPC compared to nr-NPC controls, which is characterized by low expression of CD8+ T cell infiltration and interferon-γ response. Expectedly, pathways relating to angiogenesis, hypoxia and NOTCH signaling were upregulated in the RR-NPC cohort. Interestingly, we observed a reversal of the immune phenotype from “cold” to an enrichment of effector T cell infiltration in the paired recurrences. Conclusions: Here, we present a comprehensive mutational landscape of RR-NPC, which revealed the potential role of the immune environment in modulating RR. The longitudinal immune dysregulation of the tumor microenvironment between the de novo tumors and recurrences could be a driver or passenger event during the onset of recurrence.
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来源期刊
自引率
0.00%
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审稿时长
20 weeks
期刊介绍: The Journal of Global Oncology (JGO) is an online only, open access journal focused on cancer care, research and care delivery issues unique to countries and settings with limited healthcare resources. JGO aims to provide a home for high-quality literature that fulfills a growing need for content describing the array of challenges health care professionals in resource-constrained settings face. Article types include original reports, review articles, commentaries, correspondence/replies, special articles and editorials.
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