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Chemically editable 3D tumour microenvironments to explore and exploit tumour immunity


Project Description

Immunotherapy of cancers may offer progression free survival that is not seen with conventional chemotherapies. However, immunological barriers present within the tumour reduce response rates to therapy. Recent studies have identified the tumour matrisome (the extracellular matrix and secretome) as a targetable barrier to immunity [1]. In support of this concept we identified a group of matrisome molecules we call the tumour ‘matrix index’ that is common to many cancer types, and associated with immunosuppression [2]. Members of the matrix index are densely glycosylated. Tumour-associated glycans are inhibitors of tumour infiltrating immune cells [3,4]. However, there is still a significant gap in our understanding of which glycans are involved in this process, and hence a shortfall in the development of targeted therapies. Understanding protein glycosylation in cancer is hampered by the fact glycans are secondary gene products, and therefore conventional methods of molecular and cell biology are of limited use. Recent chemical tools are revolutionising glycobiology and are ideal for studying tumour immunity. In this project we aim to combine these chemical tools with 3D tumour models to determine the nature of the immunosuppression by matrix glycosylation and identify the glycan moieties responsible. These models will be applicable for the study of immunity during tumour progression and as a platform for enhancing biotherapeutics.

Project description
Building 3D tumour microenvironments. We have established several types of 3D tumour microenvironment model made from primary human tissue. We have used these models so far in unpublished work to demonstrate that tumour extracellular matrix alone is capable of generating an immuno-suppressive phenotype in PBMC derived T-cells, and altering glycan patterns in this model (using crude enzyme treatments) further altered T-cell phenotype. These models will lend themselves well to chemical modification to probe how specific glycan structure alters tumour immunity.

Chemical editing of the tumour glycocalyx. Fine-tuning of the tumour glycan pattern in situ will be performed using chemically modified sugar building blocks. Sugars are adorned with a chemical tag that can be incorporated in cell surface glycans instead of their natural counterparts and traced by bioorthogonal “click” chemistry [5]. As a consequence, specific glycans can be functionalised with reporters such as fluorophores or enrichment tags, or photo-crosslinked to their cognate binding partners. Using these techniques, we will be able to connect glycan patterns to immune cell type and location within the 3D tumour models, exploring tumour infiltrating immune cell trafficking and phenotype. Time-lapse imaging in tumour models will be used to assess the location and phenotype of immune cells in real time. Spinning disc microscopy will allow direct visualization of the cell shape, and migration using IMARIS software. In collaboration with Prof. Burchell (KCL) and Dr Läubli (University Hospital, Basel) we will explore how altering tumour glycans using an in development biotherapy enhances current immunotherapies, such as anti-PD1.

The ideal candidate will have experience with synthetic chemistry at MSc, MRes or equivalent, and a background in biochemistry, chemical biology, or organic chemistry.

Potential research placements

1.Organic synthesis. Schumann Lab, Francis Crick Institute. Synthesis and utilisation of chemical probes that will be used to tag and alter tumour glycans in our model systems.

2.Immunity and imaging. Burchell lab, Kings College, London. Hyperion imaging mass spectrometry training, and assays for investigating glycan dependent T-cell and macrophage immunity.

3.Advanced multicellular 3D tumour models. Pearce Lab, Bart’s Cancer Institute. Generation of 3D tumour models. This will include in vitro tissue culture, patient tissue processing, immunohistochemistry, and flow cytometry.

Funding Notes

Non-EU students are not eligible to apply for this funding

References

1. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature; 2019, 554, 544-548.

2. Pearce, O. M. T. et al. Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers. Cancer Discov; 2018, 8, 304-319.

3. Beatson, R. et al. The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9. Nat Immunol; 2016, 17, 1273-1281.

4. Stanczak, M. A. et al. Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. J Clin Invest; 2018, 128, 4912-4923.

5. Schumann, B. et al. Chemical precision glyco-mutagenesis by glycosyltransferase engineering in living cells. bioRxiv prepreint; 2019, doi.org/10.1101/669861.

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