Understanding immune recognition in oral premalignant disorders (OPMDs)

Description

Oral potentially malignant disorders (OPMD) are associated with an increased risk of transformation to oral squamous cell carcinoma (OSCC). Studies report that up to 80% of OSCC develop from OPMD. No single biomarker accurately predicts malignant transformation, although several factors including lesion size, extent of epithelial dysplasia, uniformity and anatomical site are associated with an increased risk, and the time-course can be very variable. Importantly, the only effective treatment is a surgical excision, which results in a functional and aesthetic impairment. Emerging data indicate that the immune microenvironment plays an important role during malignant transformation, but to date the immune landscape in this OPMD is not completely understood. This proposal aims to characterize the immune infiltrates to segregate protective features from those that allow transformation to occur. In this project, we will benefit from access to a large cohort of OPMD patients from whom samples have been collected with a known transformation status and who are under our care for follow up. The patients come from three geographical areas where OPMD is prevalent (UK, Malaysia, and Sri Lanka). As an initial focus for the project, we have previously identified two shared tumour antigens that are expressed in invasive cancer and against which our collaborative group is deploying a novel doggy bone (db) DNA vaccine into the clinic in recurrent OSCC. This project will lay the basis for a similar approach to be used in OPMDs.

Aim & Objectives

Our overall aim is to improve our understanding of OPMD and to identify high risk patients that might benefit from therapeutic vaccination in a future early clinical trial.

Specific Objectives are:

1. To characterize the transcriptome of OPMDs, comparing lesions which transformed to OSCC with those that did not.
2. To evaluate the expression of novel tumour antigens and the overall OPMD stromal immune microenvironment using spatial proteomic techniques.

Objective 1:  200 OPMDs (100 transformed and 100 non-transformed cases) with complete clinical data and a minimal of 2 years follow up will be curated from the Pathology Departments. We will utilise immune signatures from our preliminary study to determine the immune landscape of OPMDs: Single-sample gene set enrichment analysis (ssGSEA) will be conducted and the immune cell composition in each sample will be determined using CIBERSORTx and ESTIMATE. Differential gene expression between transformed and non-transformed cases will be computed. Identified oncogenic and immune related genes will be further validated using the Phenocycler fusion system (Akoya Biosciences).

Objective 2:   We will confirm the expression of our target antigens on selected samples from our transcriptomic analysis and of our target antigens (MAGED4B and FJX1), where possible using longitudinal samples. Spatial analysis of these signatures at the protein level will be performed using multiplexed immune-histochemistry on FFPE using Phenocycler fusion system (Akoya Biosciences).  The team will work to develop custom panel inclusive of target antigens, specific transformation biomarkers identified to elucidate the interactome of different immune cells with T cells at spatial level (20-25 markers).

Outcome/Impact

To date, there are no effective biomarkers for accurate prediction of malignant transformation of OPMDs, nor is any established chemoprevention strategies routinely used in clinics. In this multicentre international cohort, we will compare the immunological features in OPMD that have progressed to invasive malignancy and non-progressors to define key features of the microenvironment that could influence the transformation potential of OPMD, as a prelude to evaluation of a novel cancer vaccine TGL100 targeting these antigens, thus setting the scene for exploitation as a preventative therapy in high risk OPMDs.

Applications

To apply please send CV and cover letter to Keith.hunter@liverpool.ac.uk