Development of an Ex-vivo Patient- Derived-Explant Model for Endometrial Cancer

Objective: To develop a novel Endometrial Cancer Patient-Derived-Explant (EC-PDE) preclinical model system that is capable of detecting patient-specific drug-responses to standard-of-care chemotherapies and immunotherapy ex vivo.

Methods: Endometrial tumour was obtained from 35 patients with endometrial cancer and processed into explants. EC-PDEs were then cultured at the air-liquid interface for up to 24 h followed by a further 24 h treatment with Carboplatin and Paclitaxel or Pembrolizumab and then processed into histology slides. Multiplexed immunofluorescence for Ki67 (proliferation marker), cPARP (apoptosis marker) and CAM 5.2 (tumour mask) was performed for viability studies and for CD8, CD4 and FOX-P3 antibodies for immune profiling studies. Images were then analysed with quantitation of biomarker expression and necrosis area.

Results: EC-PDEs maintained the histological architecture of the tumour and surrounding tumour microenvironment. EC-PDEs remained viable for up to 48 h irrespective of culture-media or serum supplementation. Differential drug-responses were detected to single- and dual-agent chemotherapy with the greatest drug-responses identified in high-risk tumours. Cell-death-responses were also identified following Pembrolizumab-treatment. Immune cell profiling in the tumour and stroma was suggestive of an immunosuppressive effect of T-regulatory cells whilst the greatest drug-responses were seen in tumours with a CD8hot phenotype.

Conclusions: EC-PDEs represent a low-cost 3D pre-clinical model which offers the potential for rapid, personalised pre-clinical drug-response testing. EC-PDEs can be used to explore the biological effects of immunotherapy and to evaluate predictors of drug response.