Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma.

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ICR Authors

Househam, Jacob
 Ronel, Tahel
 Baker, Ann-Marie Clare
 Zapata Ortiz, Luis
 Graham, Trevor

Authors

Barroux, M
Househam, J
Lakatos, E
Ronel, T
Baker, A-M
Salié, H
Mossner, M
Smith, K
Kimberley, C
Nowinski, S
Berner, A
Gunasri, V
Borgmann, M
Liffers, S
Jansen, M
Caravagna, G
Steiger, K
Slotta-Huspenina, J
Weichert, W
Zapata, L
Giota, E
Lorenzen, S
Alberstmeier, M
Chain, B
Friess, H
Bengsch, B
Schmid, RM
Siveke, JT
Quante, M
Graham, TA

Document Type

Journal Article

Date

2025-05-01

Date Accepted

2025-03-21

Abstract

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.

Citation

Nature Cancer, 2025, 6 (5), pp. 820 - 837

DOI

10.1038/s43018-025-00955-w

URI

https://repository.icr.ac.uk/handle/internal/6678

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Cancer

Publisher

NATURE PORTFOLIO

ISSN

2662-1347

eISSN

2662-1347

Collections

Genetics and Epidemiology

Research Team

Cancer Genomics
Genomics & evolut dynam
Evolutionary Immunogenom

Notes