Award Title: Restoring response to immunotherapy by targeting the extracellular matrix
Funder: Cancer Research UK

Abstract: Background  Patients with cancer that respond to immunotherapy benefit from prolonged progression free survival. Response rates vary across cancer types, with solid carcinomas generally being the poorest at between 10-20 %. Understanding the differences between responders (the 10-20%) and non-responders (the 80-90%) could identify ways to improve response rates. Targeting tumour extracellular matrix (ECM) can restore immune cell infiltration into tumour and response to immunotherapy in preclinical models. However, tumour ECM is also a protective barrier to disease progression. Therefore, targeting specific ECM components may restore immune cell infiltration without removing the barrier. We conducted a multi-level characterisation of a tumour microenvironment and identified a ECM signature, the matrix index (MI), that is prognostic in thirteen different human cancers and associates with immunosuppressive phenotypes. Moreover, my preliminary data suggest that MI molecules have altered structure in disease. I hypothesise that these disease forms of MI molecules block immune cell infiltration and therefore targeting them may improve cancer immunity.     Aims  The central aim is to improve cancer immunity by targeting MI molecules. The project focuses on triple negative breast cancer, where the MI is an especially strong feature.  We will:   • Determine which cells contribute MI molecules in the tumour microenvironment, and characterize disease forms of MI molecules, to identify targetable structural motifs.  • Identify tissue areas where one or more MI molecule correlates with T-cell exclusion from tumour parenchyma.  • Determine which MI molecule(s) and structural motifs are most important in immune cell migration.   • Test inhibiting MI molecules as a way to improve immunotherapy responsiveness.    Methods  MI molecules from patient tissues and cells will be characterized using a combination of transcriptomics and our unique tissue proteomic and glycomic pipelines. Imaging mass cytometry will be used to construct a matrix-immunity map. Engineered 3D tissue models will be used to investigate immune cell trafficking within altered tumour ECMs. Murine models which recapitulate low immune infiltrate will be used to test targeting MI molecules to restore responsiveness to immunotherapy.     How the results will be used  These results will help explain why many patients do not respond to immunotherapy. This may help clinical selection of patients most likely to respond to immunotherapy, and be used to inform the development of ECM targeted therapies. ECM characterization and target data acquired though our analysis pipeline will be made publicly available through our dedicated tumour microenvironment website (www.canbuild.org.uk).

Lay Abstract: Background  Patients with cancer that respond to immunotherapy benefit from prolonged progression free survival. Response rates vary across cancer types, with solid carcinomas generally being the poorest at between 10-20 %. Understanding the differences between responders (the 10-20%) and non-responders (the 80-90%) could identify ways to improve response rates. Targeting tumour extracellular matrix (ECM) can restore immune cell infiltration into tumour and response to immunotherapy in preclinical models. However, tumour ECM is also a protective barrier to disease progression. Therefore, targeting specific ECM components may restore immune cell infiltration without removing the barrier. We conducted a multi-level characterisation of a tumour microenvironment and identified a ECM signature, the matrix index (MI), that is prognostic in thirteen different human cancers and associates with immunosuppressive phenotypes. Moreover, my preliminary data suggest that MI molecules have altered structure in disease. I hypothesise that these disease forms of MI molecules block immune cell infiltration and therefore targeting them may improve cancer immunity.     Aims  The central aim is to improve cancer immunity by targeting MI molecules. The project focuses on triple negative breast cancer, where the MI is an especially strong feature.  We will:   • Determine which cells contribute MI molecules in the tumour microenvironment, and characterize disease forms of MI molecules, to identify targetable structural motifs.  • Identify tissue areas where one or more MI molecule correlates with T-cell exclusion from tumour parenchyma.  • Determine which MI molecule(s) and structural motifs are most important in immune cell migration.   • Test inhibiting MI molecules as a way to improve immunotherapy responsiveness.    Methods  MI molecules from patient tissues and cells will be characterized using a combination of transcriptomics and our unique tissue proteomic and glycomic pipelines. Imaging mass cytometry will be used to construct a matrix-immunity map. Engineered 3D tissue models will be used to investigate immune cell trafficking within altered tumour ECMs. Murine models which recapitulate low immune infiltrate will be used to test targeting MI molecules to restore responsiveness to immunotherapy.     How the results will be used  These results will help explain why many patients do not respond to immunotherapy. This may help clinical selection of patients most likely to respond to immunotherapy, and be used to inform the development of ECM targeted therapies. ECM characterization and target data acquired though our analysis pipeline will be made publicly available through our dedicated tumour microenvironment website (www.canbuild.org.uk).

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS