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

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

Gut

10.1136/gutjnl-2021-324420

http://dx.doi.org/10.1136/gutjnl-2021-324420

Raghav Sundar, Kie-Kyon Huang, Vikrant Kumar, Kalpana Ramnarayanan, Deniz Demircioğlu, 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

Gastroenterology

25 August 2021

Sundar, R., Huang, K.-K., Kumar, V., Ramnarayanan, K., Demircioglu, D., Her, Z., Ong, X., Bin Adam Isa, Z. F., Xing, M., Tan, A. L.-K., Tai, D. W. M., Choo, S. P., Zhai, W., Lim, J. Q., Das Thakur, M., Molinero, L., Cha, E., Fasso, M., Niger, M., … Tan, P. (2021). Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut, gutjnl-2021-324420. https://doi.org/10.1136/gutjnl-2021-324420

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation - Singapore Fellowship
Grant Reference no. : NRF-NRFF2017-03

This research / project is supported by the National Medical Research Council - NMRC Transition Award
Grant Reference no. : NMRC/TA20Nov/0014

This research / project is supported by the Duke-NUS Medical School / A*STAR - Duke NUS Block funding
Grant Reference no. : N.A

This research / project is supported by the National Medical Research Council - Open Fund - Large Collaborative
Grant Reference no. : OF-LCG18May-0023

This research / project is supported by the National Medical Research Council - NCIS Centre Grant Research Core 3
Grant Reference no. : NR13NMR111OM

This research / project is supported by the National Medical Research Council - Singapore Translational Research (STaR)
Grant Reference no. : STaR/0026/2015

https://oar.a-star.edu.sg/communities-collections/articles/18304

0017-5749
1468-3288

Institute of Molecular and Cell Biology