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Background <p>Neoadjuvant treatment (NAT) in oesophageal adenocarcinoma (EAC) is characterised by differential responses between patients and treatment modalities. The components of the tumour microenvironment (TME) that contribute to this are unknown. We explored this, focusing on cancer-associated fibroblasts (CAF) an abundant TME component.</p> Methods <p>We performed histopathologic, single-cell RNA sequencing and transcriptomic analysis on 26 patients, stratified by pathological response to NAT, and validated a prognostic model in genomic consortia cohorts. Patient-derived cells were used to model CAF phenotypes in vitro.</p> Results <p>We observed changes in the TME in response to the NAT received. Specific changes in fibroblasts correlated with treatment response and altered gene expression associated with NAT type. Three myofibroblastic phenotypes dominate the TME, two of which persist in non-responders and could only be partially re-capitulated in vitro using co-culture with cancer cells or TGF-β. A two-gene NAT fibrotic signature was an independent prognostic indicator in chemo/chemoradiotherapy treated patients (HR = 2.47, <i>p</i> = 0.029).</p> Conclusions <p>This study provides a compendium of cell phenotypes in EAC across the current NAT treatment pathway that provides insights into CAF biology and cancer progression. MyoCAFs represent an axis to repurpose agents to enhance current therapies and immunotherapy.</p>

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Cancer-associated fibroblasts are associated with neo-adjuvant treatment response in oesophageal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月10日

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  • Robert C. Walker,
  • Stella P. Breininger,
  • Benjamin P. Sharpe,
  • Jack Harrington,
  • Ian Reddin,
  • Carmen Tse,
  • Rushda Rajak,
  • Annette Hayden,
  • Saqib Rahman,
  • Ben Grace,
  • Fereshteh Izadi,
  • Jonathan West,
  • Rebecca C. Fitzgerald,
  • Paul A. W. Edwards,
  • Nicola Grehan,
  • Barbara Nutzinger,
  • Caitriona Hughes,
  • Elwira Fidziukiewicz,
  • Shona MacRae,
  • Alex Northrop,
  • Xiaodun Li,
  • Annalise Katz-Summercorn,
  • Sujath Abbas,
  • Maria O’Donovan,
  • Ahmad Miremadi,
  • Shalini Malhotra,
  • Monika Tripathi,
  • EC Smyth,
  • Simon Tavaré,
  • Andy G. Lynch,
  • Matthew Eldridge,
  • Maria Secrier,
  • Ginny Devonshire,
  • Sriganesh Jammula,
  • Aisling M. Redmond,
  • Sarah Killcoyne,
  • Amber Grantham,
  • Adrienn Blasco,
  • Jim Davies,
  • Charles Crichton,
  • Nick Carroll,
  • Peter Safranek,
  • Andrew Hindmarsh,
  • Vijayendran Sujendran,
  • J. Robert O’Neill,
  • Stephen J. Hayes,
  • Yeng Ang,
  • Andrew Sharrocks,
  • Shaun R. Preston,
  • Sarah Oakes,
  • Izhar Bagwan,
  • Vicki Save,
  • Richard J. E. Skipworth,
  • Ted R. Hupp,
  • Olga Tucker,
  • Andrew Beggs,
  • Philippe Taniere,
  • Sonia Puig,
  • Gianmarco Contino,
  • Ben L. Grace,
  • Hugh Barr,
  • Neil Shepherd,
  • Oliver Old,
  • Jesper Lagergren,
  • James Gossage,
  • Andrew Davies,
  • Fuju Chang,
  • Janine Zylstra,
  • Ula Mahadeva,
  • Vicky Goh,
  • Francesca D. Ciccarelli,
  • Grant Sanders,
  • Richard Berrisford,
  • Catherine Harden,
  • Mike Lewis,
  • Ed Cheong,
  • Bhaskar Kumar,
  • Simon L. Parsons,
  • Irshad Soomro,
  • Philip Kaye,
  • John Saunders,
  • Laurence Lovat,
  • Rehan Haidry,
  • Michael Scott,
  • Sharmila Sothi,
  • Sari Suortamo,
  • Suzy Lishman,
  • George B. Hanna,
  • Christopher J. Peters,
  • Krishna Moorthy,
  • Anna Grabowska,
  • Richard Turkington,
  • Damian McManus,
  • Helen Coleman,
  • David Khoo,
  • Will Fickling,
  • Tom D. L. Crosby,
  • Russell D. Petty,
  • Maria Secrier,
  • Zoë S. Walters,
  • Matthew J. J. Rose-Zerilli,
  • Timothy J. Underwood

摘要

Background

Neoadjuvant treatment (NAT) in oesophageal adenocarcinoma (EAC) is characterised by differential responses between patients and treatment modalities. The components of the tumour microenvironment (TME) that contribute to this are unknown. We explored this, focusing on cancer-associated fibroblasts (CAF) an abundant TME component.

Methods

We performed histopathologic, single-cell RNA sequencing and transcriptomic analysis on 26 patients, stratified by pathological response to NAT, and validated a prognostic model in genomic consortia cohorts. Patient-derived cells were used to model CAF phenotypes in vitro.

Results

We observed changes in the TME in response to the NAT received. Specific changes in fibroblasts correlated with treatment response and altered gene expression associated with NAT type. Three myofibroblastic phenotypes dominate the TME, two of which persist in non-responders and could only be partially re-capitulated in vitro using co-culture with cancer cells or TGF-β. A two-gene NAT fibrotic signature was an independent prognostic indicator in chemo/chemoradiotherapy treated patients (HR = 2.47, p = 0.029).

Conclusions

This study provides a compendium of cell phenotypes in EAC across the current NAT treatment pathway that provides insights into CAF biology and cancer progression. MyoCAFs represent an axis to repurpose agents to enhance current therapies and immunotherapy.