Wei Wang1,2, Liu-Fang Ye1,3,4, Hua Bao5, Ming-Tao Hu1,3,4, Ming Han5, Hai-Meng Tang5, Chao Ren1,3,4, Xue Wu5, Yang Shao5,6, Feng-Hua Wang1,3,4, Zhi-Wei Zhou1,2, Yu-Hong Li1,3,4, Rui-Hua Xu1,3,4, De-Shen Wang7,8,9. 1. 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. 2. Department of Gastric Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China. 3. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China. 4. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dong feng, East Road, Guangzhou, 510060, People's Republic of China. 5. Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. 6. School of Public Health, Nanjing Medical University, Nanjing, China. 7. 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. wangdsh@sysucc.org.cn. 8. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China. wangdsh@sysucc.org.cn. 9. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dong feng, East Road, Guangzhou, 510060, People's Republic of China. wangdsh@sysucc.org.cn.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.
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