University of Cambridge
Mapping the spatial organisation of B cells and immune signalling in TNBC to characterise response to immunotherapy
Abstract
dc:description.abstractIn 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.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Ahmad, Lubna
- Advisor dc:contributor.advisor
-
- Ali, Raza
Subjects
dc:subject × 8Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.127346
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/398511