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

Autor:	Sundar R; Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Hospital, Singapore gmstanp@duke-nus.edu.sg raghav_sundar@nuhs.edu.sg.; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.; The N.1 Institute for Health, National University of Singapore, Singapore.; Singapore Gastric Cancer Consortium, Singapore., Huang KK; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Kumar V; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Ramnarayanan K; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Demircioglu D; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Her Z; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore., Ong X; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Bin Adam Isa ZF; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Diagnostic Development Hub (DxD), Agency for Science, Technology and Research, Singapore., Xing M; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Diagnostic Development Hub (DxD), Agency for Science, Technology and Research, Singapore., Tan AL; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Tai DWM; Division of Medical Oncology, National Cancer Centre, Singapore., Choo SP; Division of Medical Oncology, National Cancer Centre, Singapore.; Curie Oncology, Singapore., Zhai W; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Lim JQ; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Das Thakur M; Department of Development Sciences, Genentech, San Francisco, California, USA., Molinero L; Department of Development Sciences, Genentech, San Francisco, California, USA., Cha E; Department of Development Sciences, Genentech, San Francisco, California, USA., Fasso M; Department of Development Sciences, Genentech, San Francisco, California, USA., Niger M; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Pietrantonio F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Lee J; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Jeyasekharan AD; Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Hospital, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Qamra A; Statistical Programming and Analytics, Roche Canada, Mississauga, Ontario, Canada.; University Health Network, Toronto, Ontario, Canada., Patnala R; Sci-illustrate, Munich, Germany., Fabritius A; Sci-illustrate, Munich, Germany., De Simone M; InSilico Genomics, Phoenix, Arizona, USA., Yeong J; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Ng CCY; Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore., Rha SY; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea., Narita Y; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan., Muro K; Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan., Guo YA; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Skanderup AJ; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., So JBY; Singapore Gastric Cancer Consortium, Singapore.; Department of Surgery, National University Hospital, Singapore.; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Yong WP; Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Hospital, Singapore.; Singapore Gastric Cancer Consortium, Singapore., Chen Q; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Göke J; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Tan P; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore gmstanp@duke-nus.edu.sg raghav_sundar@nuhs.edu.sg.; Singapore Gastric Cancer Consortium, Singapore.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre, Singapore.; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2022 Jul; Vol. 71 (7), pp. 1277-1288. Date of Electronic Publication: 2021 Aug 25.
DOI:	10.1136/gutjnl-2021-324420
Abstrakt:	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 APB high , APB int and APB low. 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: APB high 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 APB high tumours. Functional in vivo studies using 'humanised mice' harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APB high tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APB high tumours to immune checkpoint inhibition. APB high gastric cancer exhibited significantly poorer progression-free survival compared with APB low (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. Competing Interests: Competing interests: The subject matter in this manuscript was submitted as a technology disclosure to the institutional Technology Transfer Office for potential intellectual property protection. PT had stock and other ownership interests in HealthSeq, research funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). RS received honoraria from Bristol-Myers Squibb, Lilly, Roche, Taiho, Astra Zeneca, DKSH and MSD; had advisory activity with Bristol-Myers Squibb, Eisai, Merck, Bayer, Taiho, Novartis, MSD and AstraZeneca; received research funding from Paxman Coolers and MSD; received travel grants from AstraZeneca, Roche, Eisai and Taiho Pharmaceutical (all outside the submitted work). FP received honoraria for speakers’ bureau/advisory activity from Amgen, Merck-Serono, Roche, Lilly, Sanofi, Bayer and Servier, and received research funding from BMS (all outside the submitted work). (© 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.)
Databáze:	MEDLINE
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