TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence

作者：Alexandre Reuben, Rachel M. Gittelman, Jianjun Gao, Jiexin Zhang, Erik Yusko, Chang‐Jiun Wu, Ryan Emerson, Jianhua Zhang, Christopher M. Tipton, Jun Li, Kelly Quek, Vancheswaran Gopalakrishnan, Runzhe Chen, Luis M. Vence, Tina Cascone, Marissa Vignali, Junya Fujimoto, Jaime Rodriguez‐Canales, Edwin R. Parra, Latasha Little, Curtis Gumbs, Marie‐Andrée Forget, Lorenzo Federico, Cara Haymaker, Carmen Behrens, Sharon Benzeno, Chantale Bernatchez, Boris Sepesi, Don L. Gibbons, Jennifer A. Wargo, William N. William, Stephen G. Swisher, John V. Heymach, Harlan Robins, J. Jack Lee, Padmanee Sharma, James P. Allison, P. Andrew Futreal, Ignacio I. Wistuba, Jianjun Zhang · 发表于：Cancer Discovery · 年份：2017 · DOI：10.1158/2159-8290.cd-17-0256 · 被引用次数：237 · 研究领域：Cancer Immunotherapy and Biomarkers、Lymphoma Diagnosis and Treatment、Immunotherapy and Immune Responses

Abstract 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); 1088–97. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047