Cancer-associated fibroblasts are associated with neo-adjuvant treatment response in oesophageal adenocarcinoma
Walker RC., Breininger SP., Sharpe BP., Harrington J., Reddin I., Tse C., Rajak R., Hayden A., Rahman S., Grace B., Izadi F., West J., Petty RD., Crosby TDL., Fickling W., Khoo D., Coleman H., McManus D., Turkington R., Grabowska A., Moorthy K., Peters CJ., Hanna GB., Lishman S., Suortamo S., Sothi S., Scott M., Haidry R., Lovat L., Saunders J., Kaye P., Soomro I., Parsons SL., Kumar B., Cheong E., Lewis M., Harden C., Berrisford R., Sanders G., Ciccarelli FD., Goh V., Mahadeva U., Zylstra J., Chang F., Davies A., Gossage J., Lagergren J., Old O., Shepherd N., Barr H., Grace BL., Contino G., Puig S., Taniere P., Beggs A., Tucker O., Hupp TR., Skipworth RJE., Save V., Bagwan I., Oakes S., Preston SR., Sharrocks A., Ang Y., Hayes SJ., O’Neill JR., Sujendran V., Hindmarsh A., Safranek P., Carroll N., Crichton C., Davies J., Blasco A., Grantham A., Killcoyne S., Redmond AM., Jammula S., Devonshire G., Secrier M., Eldridge M., Lynch AG., Tavaré S., Smyth EC., Tripathi M., Malhotra S., Miremadi A., O’Donovan M., Abbas S., Katz-Summercorn A., Li X., Northrop A., MacRae S., Fidziukiewicz E., Hughes C., Nutzinger B., Grehan N., Edwards PAW., Fitzgerald RC., Secrier M., Walters ZS.
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.