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

doi:10.1136/gutjnl-2021-324420

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 PietrantonioJeeyun 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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1277-1288
Number of pages	12
Journal	Gut
Volume	71
Issue number	7
DOIs	https://doi.org/10.1136/gutjnl-2021-324420
Publication status	Published - 2022 Jul 1

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

All Science Journal Classification (ASJC) codes

Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2021-324420

Cite this

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. (2022). Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut, 71(7), 1277-1288. https://doi.org/10.1136/gutjnl-2021-324420

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title = "Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition",

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.",

author = "Raghav Sundar and Huang, {Kie Kyon} and Vikrant Kumar and Kalpana Ramnarayanan and Deniz Demircioglu and Zhisheng Her and Xuewen Ong and {Bin Adam Isa}, {Zul Fazreen} and Manjie Xing and Tan, {Angie Lay Keng} and Tai, {David Wai Meng} and Choo, {Su Pin} and Weiwei Zhai and Lim, {Jia Qi} and {Das Thakur}, Meghna and Luciana Molinero and Edward Cha and Marcella Fasso and Monica Niger and Filippo Pietrantonio and Jeeyun Lee and Jeyasekharan, {Anand D.} and Aditi Qamra and Radhika Patnala and Arne Fabritius and {De Simone}, Mark and Joe Yeong and Ng, {Cedric Chuan Young} and Rha, {Sun Young} and Yukiya Narita and Kei Muro and Guo, {Yu Amanda} and Skanderup, {Anders Jacobsen} and So, {Jimmy Bok Yan} and Yong, {Wei Peng} and Qingfeng Chen and Jonathan G{\"o}ke and Patrick Tan",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = jul,

day = "1",

doi = "10.1136/gutjnl-2021-324420",

language = "English",

volume = "71",

pages = "1277--1288",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

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Sundar, R, Huang, KK, Kumar, V, Ramnarayanan, K, Demircioglu, D, Her, Z, Ong, X, Bin Adam Isa, ZF, Xing, M, Tan, ALK, Tai, DWM, Choo, SP, Zhai, W, Lim, JQ, Das Thakur, M, Molinero, L, Cha, E, Fasso, M, Niger, M, Pietrantonio, F, Lee, J, Jeyasekharan, AD, Qamra, A, Patnala, R, Fabritius, A, De Simone, M, Yeong, J, Ng, CCY, Rha, SY, Narita, Y, Muro, K, Guo, YA, Skanderup, AJ, So, JBY, Yong, WP, Chen, Q, Göke, J & Tan, P 2022, 'Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition', Gut, vol. 71, no. 7, pp. 1277-1288. https://doi.org/10.1136/gutjnl-2021-324420

TY - JOUR

T1 - Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition

AU - Sundar, Raghav

AU - Huang, Kie Kyon

AU - Kumar, Vikrant

AU - Ramnarayanan, Kalpana

AU - Demircioglu, Deniz

AU - Her, Zhisheng

AU - Ong, Xuewen

AU - Bin Adam Isa, Zul Fazreen

AU - Xing, Manjie

AU - Tan, Angie Lay Keng

AU - Tai, David Wai Meng

AU - Choo, Su Pin

AU - Zhai, Weiwei

AU - Lim, Jia Qi

AU - Das Thakur, Meghna

AU - Molinero, Luciana

AU - Cha, Edward

AU - Fasso, Marcella

AU - Niger, Monica

AU - Pietrantonio, Filippo

AU - Lee, Jeeyun

AU - Jeyasekharan, Anand D.

AU - Qamra, Aditi

AU - Patnala, Radhika

AU - Fabritius, Arne

AU - De Simone, Mark

AU - Yeong, Joe

AU - Ng, Cedric Chuan Young

AU - Rha, Sun Young

AU - Narita, Yukiya

AU - Muro, Kei

AU - Guo, Yu Amanda

AU - Skanderup, Anders Jacobsen

AU - So, Jimmy Bok Yan

AU - Yong, Wei Peng

AU - Chen, Qingfeng

AU - Göke, Jonathan

AU - Tan, Patrick

PY - 2022/7/1

Y1 - 2022/7/1

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85128611556&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2021-324420

DO - 10.1136/gutjnl-2021-324420

M3 - Article

C2 - 34433583

AN - SCOPUS:85128611556

SN - 0017-5749

VL - 71

SP - 1277

EP - 1288

JO - Gut

JF - Gut

IS - 7

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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