Characterising the Glycan Shield

Researcher: Dr Oliver Pearce

Location: Barts Cancer Institute, London

Dates:  Feb 2018 – Feb 2019     Status: Complete

Funding: £45,256

Research Theme: Therapies, Detection

Aims

The Glycan Shield project at Barts Cancer Institute in London lead by Dr. Oliver Pearce, aims to identify how breast cancer tumours remodel their surroundings to protect them from attack by the bodies’ own immune system.

Sugar structures (glycans) are altered in cancer, but it is not fully understood what kind of glycan changes occur and how these changes protect cancer cells from destruction by the immune system. Dr. Pearce hypothesizes that abnormal glycans in the extracellular matrix (ECM) deactivate immune cells, turning off their cell-killing function.

Background

The extracellular matrix is a scaffold of different molecules that make up the tissues surrounding cells. During invasive cancer growth the ECM is remodelled by the tumour, by  breaking down the tissue basement membrane and expressing unusual ECM proteins within the tumour microenvironment. The resulting tumour ECM is important because it relates to how the tumour grows and interacts with host cells. Compared to our understanding of malignant and immune cells, the tumour ECM and the cells that produce it are an under-investigated area of cancer biology. The identity, role in tumour progression, mechanisms of production, and therapeutic potential of the components that make up the tumour ECM are all important for our understanding of the tumour microenvironment. 

Towards this goal Dr. Pearce recently carried out a detailed study focusing on the ECM components within an evolving tumour microenviroment (Pearce et al, Cancer Discovery, 2018). Here they identified the ‘Matrix Index’ (MI), a quantitative measure identifying particular proteins of the tumour ECM in high grade serous ovarian cancer. As part of this study they found that the MI appears to be common to many cancers, and was particularly strong in triple negative breast cancer (TNBC).

The aim of this Glycan Shield project is to further investigate the MI proteins in triple negative breast cancer tissues. In collaboration with Dr. Alexandra Naba (University of Illinois, Chicago), Dr. Pedro Cutillas (QMUL), and Dr. Stuart Haslam (Imperial College, London), this will be the first highly detailed study of the components that make up the ECM of triple negative breast cancer, including characterising both the protein and glycan modifications which may deactivate immune cells, stopping them from destroying the tumour.

Potential benefit for patients

Unique matrix protein structures that we hope to identify may have the potential for further development as targeting molecules for the delivery of new anticancer agents, or the target of therapeutic antibodies for ECM-focused cancer therapies. If ECM alterations happen early in tumour growth then they might also be developed as prognostic biomarkers of disease.

Currently, immunotherapy treatment for solid tumours such as triple negative breast cancer, only works well in around 10-15% of patients. Through an understanding of the tumour extracellular matrix, and the glycan shield it displays, we hope to improve breast cancer treatment and increase the immunotherapy response rates for all patients.

Project Results and Impact

Dr Pearce used his project grant from ABC to successfully gather preliminary data necessary to support a larger grant application. He has now been awarded a CRUK Career Establishment Award of over £800,000 to continue and develop his work for a further six years.  

Project outcomes have included: 

• First of its kind data sets of protein and glycan analyses on TNBC tissues. This valuable data will be added to the open access databases PRIDE (proteins) and UniCarb (glycans) for other scientists to be able to use.  

• Development of 3D tissue models for testing cell interactions with ECM molecules. This will help to more closely represent what happens in a patient and make research results more relevant. 
• Determined that the tumour ECM does causes immune cell (T-cell) exhaustion, and ECM glycans further alter how immune cells look and function. This validates Dr Pearce’s original hypothesis that the glycan shield does affect immune cell function. 
• Identified matrix index proteoglycan VCAN as a potential target for improving anti-tumour immunity.  
• Generating antibodies against MI molecules, and in particular VCAN, which in the long term could be used as part of a therapeutic approach to improve anti-cancer immunity.  

Following on from this project, VCAN is now being studied further as part of a 4-year PhD project. We are continuing our support of Dr Pearce’s work by helping to co-fund this exciting PhD research project.

“The seed grant from Against Breast Cancer allowed us to take an idea and accelerate it forward effectively finishing a project that would otherwise have taken several years.”

Dr Oliver Pearce 

Q&A, discussing detection and the Glycan Shield project

As part of our regular Research Q&A series, Dr Pearce took the time to answer questions about his research which were posed by supporters of Against Breast Cancer;

Publications

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers. Pearce OMT, Delaine-Smith RM, Maniati E, Nichols S, Wang J, Böhm S, Rajeeve V, Ullah D, Chakravarty P, Jones RR, Montfort A, Dowe T, Gribben J, Jones JL, Kocher HM, Serody JS, Vincent BG, Connelly J, Brenton JD, Chelala C, Cutillas PR, Lockley M, Bessant C, Knight MM, Balkwill FR. Cancer Discov. 2018 Mar;8(3):304-319. doi: 10.1158/2159-8290.CD-17-0284. Epub 2017 Dec 1.