Activated ATF6α is a hepatic tumour driver restricting immunosurveillance
Abstract
Abstract Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies 1 . Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear 2 . Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress 3 . ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB) 4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.
Article Details
Authors (98)
Xin Li
Cynthia Lebeaupin
Aikaterini Kadianaki
Clementine Druelle-Cedano
Niklas Vesper
Charlotte Rennert
Júlia Huguet-Pradell
Borja Gomez Ramos
Chaofan Fan
Robert Stefan Piecyk
Laimdota Zizmare
Pierluigi Ramadori
Luqing Li
Lukas Frick
Menjie Qiu
Cangang Zhang
Luiza Martins Nascentes Melo
Vikas Prakash Ranvir
Peng Shen
Johannes Hanselmann
Jan Kosla
Mirian Fernández-Vaquero
Mihael Vucur
Praveen Baskaran
Xuanwen Bao
Olivia I. Coleman
Yingyue Tang
Miray Cetin
Zhouji Chen
Insook Jang
Stefania Del Prete
Mohammad Rahbari
Peng Zhang
Timothy V. Pham
Yushan Hou
Aihua Sun
Li Gu
Laura C. Kim
Ulrike Rothermel
Danijela Heide
Adnan Ali
Suchira Gallage
Nana Talvard-Balland
Marta Piqué-Gili
Albert Gris-Oliver
Alessio Bevilacqua
Lisa Schlicker
Alec Duffey
Kristian Unger
Marta Szydlowska
Jenny Hetzer
Duncan T. Odom
Tim Machauer
Daniele Bucci
Pooja Sant
Jun-Hoe Lee
Jonas Rösler
Sven W. Meckelmann
Johannes Schreck
Sue Murray
M. Celeste Simon
Sven Nahnsen
Almut Schulze
Ping-Chih Ho
Manfred Jugold
Kai Breuhahn
Jan-Philipp Mallm
Peter Schirmacher
Susanne Roth
Nuh Rahbari
Darjus F. Tschaharganeh
Stephanie Roessler
Benjamin Goeppert
Bertram Bengsch
Geoffroy Andrieux
Melanie Boerries
Nisar P. Malek
Marco Prinz
Achim Weber
Robert Zeiser
Pablo Tamayo
Peter Bronsert
Konrad Kurowski
Robert Thimme
Detian Yuan
Rafael Carretero
Tom Luedde
Roser Pinyol
Felix J. Hartmann
Michael Karin
Alpaslan Tasdogan
Christoph Trautwein
Moritz Mall
Maike Hofmann
Josep M. Llovet
Dirk Haller
Randal J. Kaufman
Mathias Heikenwälder