State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, 510060, People's Republic of China.
Department of Gastric Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
Gastric Cancer. 2022 Nov;25(6):1017-1030. doi: 10.1007/s10120-022-01324-7. Epub 2022 Jul 29.
Tumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past.
Together with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals.
We discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient.
Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.
肿瘤免疫微环境异质性在许多癌症中普遍存在，并可能对免疫治疗反应产生负面影响。过去并未研究过胃食管腺癌（GEA）中的免疫异质性和进化。
我们与正常、原发性和转移性组织的多区域采样一起，进行了全外显子测序、TCR 测序以及通过基因表达信号解卷积来估计免疫细胞浸润。
我们发现转移性部位之间存在高 TCR 库和免疫细胞浸润异质性，而原发性和正常样本之间则具有同质性。转移性部位与血液共享高水平的丰富 TCR 克隆型，表明通过血液进行免疫监视。与正常和原发性肿瘤组织相比，转移性部位的肿瘤杀伤性免疫细胞水平较低，且正在进行强烈的免疫调节。新抗原和 TCR 库存在共同进化，但仅在发生晚期突变进化的患者中存在。除了一名患者外，所有患者均观察到 TCR 库和免疫细胞浸润的共同进化。
我们的发现揭示了 GEA 中的免疫异质性和共同进化，这可能为免疫治疗决策提供信息。
