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Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition

 Raghav Sundar  ;  Kie-Kyon Huang  ;  Vikrant Kumar  ;  Kalpana Ramnarayanan  ;  Deniz Demircioglu  ;  Zhisheng Her  ;  Xuewen Ong  ;  Zul Fazreen Bin Adam Isa  ;  Manjie Xing  ;  Angie Lay-Keng Tan  ;  David Wai Meng Tai  ;  Su Pin Choo  ;  Weiwei Zhai  ;  Jia Qi Lim  ;  Meghna Das Thakur  ;  Luciana Molinero  ;  Edward Cha  ;  Marcella Fasso  ;  Monica Niger  ;  Filippo Pietrantonio  ;  Jeeyun Lee  ;  Anand D Jeyasekharan  ;  Aditi Qamra  ;  Radhika Patnala  ;  Arne Fabritius   ;  Mark De Simone  ;  Joe Yeong  ;  Cedric Chuan Young Ng  ;  Sun Young Rha  ;  Yukiya Narita  ;  Kei Muro  ;  Yu Amanda Guo  ;  Anders Jacobsen Skanderup  ;  Jimmy Bok Yan So  ;  Wei Peng Yong  ;  Qingfeng Chen  ;  Jonathan Göke  ;  Patrick Tan 
 GUT, Vol.71(7) : 1277-1288, 2022-07 
Journal Title
Issue Date
Animals ; Epigenesis, Genetic ; Epigenomics ; Gastrointestinal Neoplasms* / genetics ; Gastrointestinal Neoplasms* / therapy ; Humans ; Immune Checkpoint Inhibitors / pharmacology ; Immune Checkpoint Inhibitors / therapeutic use ; Immunotherapy ; Mice ; Stomach Neoplasms* / drug therapy ; Stomach Neoplasms* / therapy ; Tumor Microenvironment
gastric cancer ; hepatocellular carcinoma ; immunotherapy
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
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