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Patient-Derived Precision Cut Tissue Slices from Primary Liver Cancer as a Suitable Platform for Preclinical Drug Testing
35 Pages Posted: 6 Dec 2022
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Patient-Derived Precision Cut Tissue Slices from Primary Liver Cancer as a Suitable Platform for Preclinical Drug Testing
Abstract
Background: The exploitation of anti-tumour immunity, harnessed through immunomodulatory therapies, has fundamentally changed the treatment of primary liver cancer (PLC). However, this has posed significant challenges in preclinical research. Novel immunologically relevant models for PLC are urgently required to improve the translation from bench to bedside and back, explore and predict effective combinatorial therapies, aid novel drug discovery and develop personalised treatment modalities.
Methods: We used Precision-cut tissue slices (PCTS) derived from resected tumours to create a patient-specific immunocompetent disease model that captures the multifaceted and intricate heterogeneity of the tumour and the tumour microenvironment. Tissue architecture, tumour viability and treatment response to single agent and combination therapies were assessed longitudinally over 8 days of ex vivo culture by histological analysis, detection of proliferation/cell death markers, ATP content via HPLC. Genetic stability and immune cell infiltrate were assessed using whole exome sequencing, PCR and immunofluorescence. Checkpoint receptor expression via Quantigene.
Finding: After optimising the culture conditions, PCTS maintained the original tissue architecture, including tumour morphology, stroma and tumour-infiltrated leukocytes. Moreover, PCTS retained clonal stability and the tumour-specific immunophenotype over time. We further demonstrated the utility of PCTS to investigate immunotherapeutic drug efficacy and identify non-response in PCTS generated from tumours with heavily exhausted or non-exhausted immunophenotypes.
Interpretation: Here we have characterised the PCTS model and demonstrated its effectiveness as a robust preclinical tool that will significantly support the development of successful (immuno)therapeutic strategies for PLC.
Funding Information: Foundation for Liver Research, London.
Declaration of Interests: The authors declare no conflict of interest.
Ethics Approval Statement: Patients undergoing partial hepatectomy, as treatment for primary liver cancer, were enrolled and written informed consent was obtained for all the subjects involved in this study (Table 1 for clinical characteristics). This study was approved by the local Research Ethics Committee established by the Health Research Authority (REC reference 17/NE/0340; IRAS project ID 222302).
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