Utilising Patient-Derived Explants to Elucidate Mechanisms of Resistance to PD-1/PD-L1 Inhibitors

About the Project

Project Summary

Immune checkpoint inhibitors targeting PD-1 and PD-L1 have transformed the therapeutic landscape for several solid cancers. Despite these advances, only a minority of patients experience durable clinical benefit. Both primary and acquired resistance remains a major barrier to effective treatment, and the underlying biological determinants are not yet fully understood. This project aims to leverage patient-derived explant (PDE) cultures as an ex vivo platform to investigate tumour-intrinsic and microenvironmental factors that drive differential responses to PD-1/PD-L1 blockade.

Background and Rationale

Checkpoint blockade efficacy relies on a complex interplay between tumour cells, infiltrating immune populations, tumour-associated stromal cells, and extracellular signalling networks. Conventional preclinical systems such as 2D cancer cell lines and mouse models lack the architectural, immunological, and stromal complexity necessary to accurately model human responses to immunotherapy. PDE systems preserve the three-dimensional structure, cellular heterogeneity, native extracellular matrix, and endogenous immune contexture of human tumours. This makes them uniquely suited for studying patient-specific immunological responses and mechanisms of drug resistance.

Despite many tumours being highly immunogenic, only a subset of patients responds to PD-1/PD-L1 inhibition. Resistance may arise from tumour-intrinsic pathways (e.g., defective antigen presentation, oncogenic signalling), microenvironmental barriers (e.g., immunosuppressive myeloid cells, fibroblast-mediated exclusion), or adaptive responses triggered by therapy. By analysing immunotherapy treated PDEs derived from fresh surgical resections, this project will enable systematic investigation of these factors in a physiologically relevant human context.

Research Design, Methods and skills learnt

Fresh tumour samples will be obtained from consenting patients undergoing tumour resection. Explants will be prepared as 2–3 mm³ fragments and cultured on filter inserts at the air liquid interface to preserve tissue architecture, then treated with immunotherapies ex vivo, prior to fixation and FFPE embedding. FFPE sections will be used to assess efficacy, and the tumour-immune interactions post treatment, using multiplexed immunofluorescence, immunohistochemistry, digital pathology, advanced image analysis, and bioinformatics. Data will be integrated using machine learning tools to identify convergent predictors of resistance and potential therapeutic vulnerabilities.

Expected Outcomes and Impact

This project will deliver a translationally relevant platform for dissecting mechanisms of immune checkpoint inhibitor resistance. Insights gained may inform patient stratification strategies, suggest biomarkers for therapeutic decision-making, and identify combination therapies capable of converting non-responders into responders. Ultimately, the work has the potential to improve precision immunotherapy and contribute to personalised cancer treatment.

Apply at:

https://le.ac.uk/study/research-degrees/research-subjects/cancer-studies

PhD entry requirements:https://le.ac.uk/study/research-degrees/entry-reqs

Supervisor contact details:

Dr Gareth Miles - gjm14@leicester.ac.uk

Dr Giuditta Viticchie - Gv51@leicester.ac.uk