Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition
| Autor: | Edward Cha, Su Pin Choo, Sun Young Rha, Kei Muro, Anand D. Jeyasekharan, Arne Fabritius, Joe Yeong, Manjie Xing, Filippo Pietrantonio, Angie Lay-Keng Tan, Aditi Qamra, Zul Fazreen Adam Isa, Kalpana Ramnarayanan, Jimmy Bok Yan So, Mark De Simone, Yukiya Narita, Radhika Patnala, Monica Niger, David Tai, Jonathan Göke, Luciana Molinero, Jeeyun Lee, Kie-Kyon Huang, Deniz Demircioğlu, Yu Amanda Guo, Meghna Das Thakur, Wei Peng Yong, Qingfeng Chen, Patrick Tan, Marcella Fassò, Zhisheng Her, Vikrant Kumar, Xuewen Ong, Weiwei Zhai, Cedric Chuan Young Ng, Jia Qi Lim, Anders Jacobsen Skanderup, Raghav Sundar |
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| Rok vydání: | 2021 |
| Předmět: |
Epigenomics
medicine.medical_treatment Gastroenterology Cancer Immunotherapy Biology medicine.disease Immune checkpoint Epigenesis Genetic Mice Immune system Stomach Neoplasms In vivo Hepatocellular carcinoma Tumor Microenvironment Cancer research medicine Animals Humans sense organs Epigenetics Immune Checkpoint Inhibitors Gastrointestinal Neoplasms |
| Zdroj: | Gut. 71:1277-1288 |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | ObjectivesEpigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours.DesignAlternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes.ResultsAPBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032).ConclusionThese findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance. |
| Databáze: | OpenAIRE |
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