Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma
Locally advanced esophageal adenocarcinoma remains difficult to treat and the ecological and evolutionary dynamics responsible for resistance and recurrence are incompletely understood. Here, we performed longitudinal multiomic analysis of patients with esophageal adenocarcinoma in the MEMORI trial. Multi-region multi-timepoint whole-exome and paired transcriptome sequencing was performed on 27 patients before, during and after neoadjuvant treatment. We found major transcriptomic changes during treatment with upregulation of immune, stromal and oncogenic pathways. Genetic data revealed that clonal sweeps through treatment were rare. Imaging mass cytometry and T cell receptor sequencing revealed remodeling of the tumor microenvironment during treatment. The presence of genetic immune escape, a less-cytotoxic T cell phenotype and a lack of clonal T cell expansions were linked to poor treatment response. In summary, there were widespread transcriptional and environmental changes through treatment, with limited clonal replacement, suggestive of phenotypic plasticity.
Authors
- Sylvie Lorenzen
- Katja Steiger (ORCID: https://orcid.org/0000-0002-7269-5433)
- Martin Borgmann (ORCID: https://orcid.org/0000-0002-8195-2796)
- Helmut Friess
- Wilko Weichert (ORCID: https://orcid.org/0000-0001-6139-8372)
- Melissa Schmidt (ORCID: https://orcid.org/0000-0002-7682-0932)
- Salpie Nowinski (ORCID: https://orcid.org/0000-0001-5686-3778)
- Giulio Caravagna (ORCID: https://orcid.org/0000-0003-4240-3265)
- Jacob Househam (ORCID: https://orcid.org/0000-0003-3199-336X)
- Bertram Bengsch (ORCID: https://orcid.org/0000-0003-2552-740X)
- Markus Alberstmeier
- Trevor A. Graham (ORCID: https://orcid.org/0000-0001-9582-1597)
- Benny Chain (ORCID: https://orcid.org/0000-0002-7417-3970)
- Michael Quante (ORCID: https://orcid.org/0000-0002-8497-582X)
- Henrike Salié (ORCID: https://orcid.org/0000-0002-2993-3782)
- Ann‐Marie Baker (ORCID: https://orcid.org/0000-0001-8905-9137)
- Kane Smith (ORCID: https://orcid.org/0000-0002-8661-7401)
- Vinaya Gunasri (ORCID: https://orcid.org/0000-0002-9292-6470)
- Eszter Lakatos (ORCID: https://orcid.org/0000-0002-7221-6850)
- Christopher Kimberley (ORCID: https://orcid.org/0000-0002-9720-4434)
- Jens Thomas Siveke (ORCID: https://orcid.org/0000-0002-8772-4778)
- Maximilian Mossner (ORCID: https://orcid.org/0000-0001-9751-3803)
- Julia Slotta‐Huspenina (ORCID: https://orcid.org/0000-0003-0057-2263)
- Alison Berner (ORCID: https://orcid.org/0000-0002-1132-0275)
- Marnix Jansen (ORCID: https://orcid.org/0000-0003-0645-564X)
- Luís Zapata (ORCID: https://orcid.org/0000-0002-1386-2019)
- Tahel Ronel (ORCID: https://orcid.org/0000-0002-9513-9181)
- Eleftheria Giota
- Roland M. Schmid (ORCID: https://orcid.org/0000-0002-5751-7313)
- Sven T. Liffers
Institutions
- University of Trieste (IT)
- Institute of Cancer Research (GB)
- University of Freiburg (DE)
- Queen Mary University of London (GB)
- German Cancer Research Center (DE)
- University Medical Center Freiburg (DE)
- Cancer Research UK (GB)
- TUM Klinikum (DE)
- Institut für Urheber- und Medienrecht (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University College London (GB)
- University of Duisburg-Essen (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s43018-025-00955-w
- Citations
- 10
- Primary Topic
- Esophageal Cancer Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 20.06
Funders
- Cancer Research UK
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe
- Deutschen Konsortium für Translationale Krebsforschung