Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma
Year: 2025
Type: article
Abstract: Locally advanced oesophageal adenocarcinoma (EAC) remains difficult to treat because of common resistance to neoadjuvant therapy and high recurrence rates. The ecological and evolutionary dynamics responsible for treatment failure are incompletely understood. Here, we performed a comprehensive multi-omic analysis of samples collected from EAC patients in the MEMORI clinical trial, revealing major changes in gene expression profiles and immune microenvironment composition that did not appear to be driven by changes in clonal composition. Multi-region multi-timepoint whole exome (300x depth) and paired transcriptome sequencing was performed on 27 patients pre-, during and after neoadjuvant treatment. EAC showed major transcriptomic changes during treatment with upregulation of immune and stromal pathways and oncogenic pathways such as KRAS, Hedgehog and WNT. However, genetic data revealed that clonal sweeps were rare, suggesting that gene expression changes were not clonally driven. Additional longitudinal image mass cytometry was performed in a subset of 15 patients and T-cell receptor sequencing in 10 patients, revealing remodelling of the T-cell compartment during treatment and other shifts in microenvironment composition. The presence of immune escape mechanisms and a lack of clonal T-cell expansions were linked to poor clinical treatment response. This study identifies profound transcriptional changes during treatment with limited evidence that clonal replacement is the cause, suggesting phenotypic plasticity and immune dynamics as mechanisms for therapy resistance with pharmacological relevance.
Source: Nature Cancer
Authors: Melissa Barroux, Jacob Househam, Eszter Lakatos, Tahel Ronel, Ann-Marie Baker, Henrike Salié, Maximilian Mossner, Kane Smith, Chris Kimberley, Salpie Nowinski, Alison Berner, Vinaya Gunasri, Martin Borgmann, Sven Liffers, Marnix Jansen, Giulio Caravagna, Katja Steiger, Julia Slotta-Huspenina, Wilko Weichert, Luis Zapata, Eleftheria Giota, Sylvie Lorenzen, Markus Alberstmeier, Benny Chain, Helmut Friess, Bertram Bengsch, Roland M. Schmid, Jens T. Siveke, Michael Quante, Trevor A. Graham
Institutions: Queen Mary University of London, TUM Klinikum, Deutsches Konsortium für Translationale Krebsforschung, Barts Cancer Institute, Technical University of Munich, Institute of Cancer Research, University College London, University Medical Center Freiburg, German Cancer Research Center, Essen University Hospital, University of Duisburg-Essen, University of Trieste, Pathologisches Institut, LMU Klinikum, Ludwig-Maximilians-Universität München, University of Freiburg
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Bristol-Myers Squibb, AstraZeneca, Celgene, Cancer Research UK, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Servier, Deutschen Konsortium für Translationale Krebsforschung, National Institutes of Health, Genentech, National Cancer Institute
Awards: G2761940787, Arizona Cancer and Evolution Center (ACE), G6165086918, Verbund SATURN3 - Räumliche und zeitliche Auflösung der intratumoralen Heterogenität bei den drei schwer zu behandelnden Krebsarten Brustkrebs, Darmkrebs und Bauchspeicheldrüsenkrebs, Standort Universität Essen-Duisburg, G7288598144, G7790726129, G8482385449, KFO 337: Phänotypische Therapie und Immunresistenz in Krebs (PhenoTImE): Präklinischer und translationaler Fortschritt der KFO 337, G868862665, G9000276717, G960497557
OpenAlex ID: W4410375588