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.

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。