Spatial-BrTME: Multicellular spatial dynamics of immunotherapy response in breast cancer

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Immunotherapy has revolutionised cancer treatment, but its role in breast cancer is unclear. For breast cancer patients to benefit, we must understand why some respond whereas others don't, and identify a pragmatic biomarker to distinguish between them. Immunotherapy depends on spatial organisation of the tumour microenvironment (TME) because it targets T cell interactions, but the principles of TME organisation are poorly understood. How immunotherapy remodels this structure during treatment is also unknown but may explain why responses differ. To understand immunotherapy response in breast cancer, and to uncover a reliable discriminatory biomarker, I propose to dissect multicellular TME structure in situ by highly multiplexed imaging of tissues. Imaging mass cytometry (IMC) uses time-of-flight mass spectrometry to localise the expression of 44 proteins at subcellular resolution in tissues. Using IMC, we will analyse thousands of samples from hundreds of breast cancer patients recruited to randomised trials of immunotherapy where longitudinal samples (at baseline, on-treatment, and post-treatment) have been collected. Using automated image analysis, graph theory and spatial statistics we will identify multicellular configurations that recur across tumours and chart how these evolve under therapy in responders versus non-responders. Findings arising from these analyses are disconnected from routine clinical pathology however, because equivalent assays are not possible in that setting, frustrating translation. We will bridge this gap by using the large digital pathology resource accrued for these trials to develop novel machine-learning tools to transfer features learned in high-dimensional space to routine digital pathology stains. Together, this programme will elucidate the pathologic basis of immunotherapy response and take first steps toward a new clinical discipline of augmented pathology.