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Title: Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition
Authors: Sundar, Raghav 
Huang, Kie-Kyon
Kumar, Vikrant 
Ramnarayanan, Kalpana
Demircioglu, Deniz
Her, Zhisheng
Ong, Xuewen 
Isa, Zul Fazreen Bin Adam 
Xing, Manjie
Tan, Angie Lay-Keng 
Tai, David Wai Meng
Choo, Su Pin
Zhai, Weiwei
Lim, Jia Qi
Das Thakur, Meghna
Molinero, Luciana
Cha, Edward
Fasso, Marcella
Niger, Monica
Pietrantonio, Filippo
Lee, Jeeyun
Jeyasekharan, Anand D 
Qamra, Aditi
Patnala, Radhika
Fabritius, Arne
De Simone, Mark
Yeong, Joe
Ng, Cedric Chuan Young
Rha, Sun Young
Narita, Yukiya
Muro, Kei
Guo, Yu Amanda
Skanderup, Anders Jacobsen
So, Jimmy Bok Yan 
Yong, Wei Peng
Chen, Qingfeng
Goke, Jonathan
Tan, Patrick 
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
gastric cancer
hepatocellular carcinoma
Issue Date: 25-Aug-2021
Citation: Sundar, Raghav, Huang, Kie-Kyon, Kumar, Vikrant, Ramnarayanan, Kalpana, Demircioglu, Deniz, Her, Zhisheng, Ong, Xuewen, Isa, Zul Fazreen Bin Adam, Xing, Manjie, Tan, Angie Lay-Keng, Tai, David Wai Meng, Choo, Su Pin, Zhai, Weiwei, Lim, Jia Qi, Das Thakur, Meghna, Molinero, Luciana, Cha, Edward, Fasso, Marcella, Niger, Monica, Pietrantonio, Filippo, Lee, Jeeyun, Jeyasekharan, Anand D, Qamra, Aditi, Patnala, Radhika, Fabritius, Arne, De Simone, Mark, Yeong, Joe, Ng, Cedric Chuan Young, Rha, Sun Young, Narita, Yukiya, Muro, Kei, Guo, Yu Amanda, Skanderup, Anders Jacobsen, So, Jimmy Bok Yan, Yong, Wei Peng, Chen, Qingfeng, Goke, Jonathan, Tan, Patrick (2021-08-25). Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. GUT 71 (7) : 1277-1288. ScholarBank@NUS Repository.
Abstract: OBJECTIVES: Epigenomic 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. DESIGN: Alternate 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. RESULTS: APBhigh 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). CONCLUSION: These findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.
Source Title: GUT
ISSN: 0017-5749
DOI: 10.1136/gutjnl-2021-324420
Appears in Collections:Staff Publications

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