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Mapping the spatial organisation of B cells and immune signalling in TNBC to characterise response to immunotherapy https://doi.org/10.17863/CAM.127346 Ahmad, Lubna Ali, Raza In recent years, B cells and tertiary lymphoid structures (TLS) have emerged as key predictors of immunotherapy response across multiple cancers. B cells exist in various states of spatial organisation within the tumour microenvironment (TME), which likely support many of their functional roles. However, the landscape of B cell spatial organisation in cancer and specifically in triple-negative breast cancer (TNBC) is poorly characterised. Organisation and function are processes that are likely orchestrated by diverse immune signalling, but what the interplay between organisation and its underlying signalling is, remains largely uncharacterised in cancer, underscoring the need for a comprehensive and systematic investigation. To characterise the spatial landscape of B cells and immune signalling, we implemented a novel approach for the simultaneous detection of protein and RNA in situ using imaging mass cytometry. We applied this assay to a randomised immunotherapy clinical trial, NeoTRIP, in which patients with TNBC were treated with atezolizumab. Samples were collected from 268 patients at three timepoints: baseline, on-treatment, and post-treatment. This study found that numerous B and Plasma cell densities were significantly associated with response to immunotherapy on-treatment. We showed that distinct B and plasma cell niches exist in TNBC, and that specifically, Germinal centre (GC) and B activated niche cell densities were a strong predictor of immunotherapy response. Additionally, we found that many B and plasma to TME interactions were also enriched among immunotherapy responders. These findings were complemented by strong treatment-induced cellular dynamics. Strikingly, the most marked increase in cell phenotype abundance in immunotherapy responders was observed in B cells, suggesting that, specifically, effective immunotherapy is inducing the expansion of B cells following treatment. We subsequently showed that cytokines behave in a spatially coordinated manner in the TME, being significantly enriched in the vicinity of the observed B and plasma cell niches. Cytokine expression mirrored the observed immune expansion seen on-treatment and was also associated with response. Specifically, cytokine-enriched niches appeared to be a feature of immunotherapy responders, suggesting that together organisation and signalling play an important role in treatment responses. Together, our findings highlight a previously unexplored diversity of B cell spatial organisation and its associated immune signalling in TNBC, most importantly showing that B cells are strong predictors of immunotherapy response. University of Cambridge 2025-09-30 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/398511 embargo 2027-02-23 https://www.repository.cam.ac.uk/bitstreams/66a1bfc8-4b9a-485b-9aed-7dd293c59a4b/download 69c35e966ba08858db85e5f80a0b4526 https://www.repository.cam.ac.uk/bitstreams/7f1c8084-8806-4393-a670-0b067dac5bb9/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved B cell Breast Cancer Imaging Immunotherapy Spatial biology Spatial organisation TNBC Treatment response