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TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: an Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence
Cancer Discovery ( IF 29.7 ) Pub Date : 2017-01-01 , DOI: 10.1158/2159-8290.cd-17-0256
Alexandre Reuben 1, 2 , Rachel Gittelman 3 , Jianjun Gao 4 , Jiexin Zhang 5 , Erik C. Yusko 3 , Chang-Jiun Wu 2 , Ryan Emerson 3 , Jianhua Zhang 2 , Christopher Tipton 3 , Jun Li 2 , Kelly Quek 2, 6 , Vancheswaran Gopalakrishnan 1 , Runzhe Chen 2, 6 , Luis M. Vence 7 , Tina Cascone 6 , Marissa Vignali 3 , Junya Fujimoto 8 , Jaime Rodriguez-Canales 8 , Edwin R. Parra 8 , Latasha D. Little 2 , Curtis Gumbs 2 , Marie-Andrée Forget 9 , Lorenzo Federico 9 , Cara Haymaker 9 , Carmen Behrens 8 , Sharon Benzeno 3 , Chantale Bernatchez 9 , Boris Sepesi 10 , Don L. Gibbons 6 , Jennifer A. Wargo 1, 2 , William N. William 6 , Stephen Swisher 10 , John V. Heymach 6 , Harlan Robins 3, 11 , J. Jack Lee 12 , Padmanee Sharma 4, 7 , James P. Allison 7 , P. Andrew Futreal 2 , Ignacio I. Wistuba 8 , Jianjun Zhang 2, 6
Affiliation  

Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.

SIGNIFICANCE: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1–10. ©2017 AACR.



中文翻译:

在局部肺腺癌中TCR保留库内肿瘤异质性:与预测的新抗原异质性和术后复发的关联。

基因组肿瘤内异质性(ITH)可能与局部肺腺癌的术后复发有关。近来,通过产生新抗原的突变显示出可通过T细胞反应改变肿瘤的免疫原性。在这里,我们对11个局灶性肺腺癌的45个肿瘤区域中的T细胞受体(TCR)进行了测序,并观察到肿瘤内T细胞密度和克隆性存在实质性差异,而大多数T细胞克隆均局限于单个肿瘤区域。TCR ITH与预测的新抗原ITH正相关,表明T细胞库中的空间差异可能是由不同肿瘤区域中不同的新抗原驱动的。最后,较高的TCR ITH程度与术后复发风险增加和无病生存期缩短有关,

意义:本研究提供了对局部肺腺癌中T细胞库的ITH及其潜在生物学和临床影响的见解。结果表明,T细胞库ITH可能与基因组ITH和疾病复发紧密相关。巨蟹座Discov; 7(10);1-10。©2017 AACR。

更新日期:2017-09-15
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