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

Lead Research Organisation: UNIVERSITY OF CAMBRIDGE
Department Name: Cancer Research UK Cambridge Institute

Abstract

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.

Publications

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Ali HR (2024) Spatial Biology of Breast Cancer. in Cold Spring Harbor perspectives in medicine

 
Description Chair at the International Symposium , Women Cancer Programme , Cambridge March 2025 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr H. Raza Ali was invited to chair at the International SYMPOSIUM Data driven discovery for women+s cancers
CRUK Cambridge Centre •Women+s Cancers Programme Location: Graduate Cambridge
Date: 13-14/03/2025 Time: 9.00 - 16.00
Year(s) Of Engagement Activity 2025
 
Description Joint CRUK CI Institute and Centre Retreat, Lecture Theatre, Cancer Research UK Cambridge Institute 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Dr H. Raza Ali participated in this important opportunity for research groups to share their work, address research challenges and for all staff to be reunited in our primary mission to beat cancer sooner.
Year(s) Of Engagement Activity 2024