Baig, Zara; (2025) Exploring the B Cell Landscape in Renal Cell Carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The rising incidence of renal cell carcinoma (RCC), coupled with poor survival rates in metastatic disease, highlights the urgent need for more effective, targeted therapies. While intratumoural B cells have been increasingly identified across various cancer types, the functional characterisation of B cell subsets remains incomplete. In particular, the immunosuppressive role of regulatory B cells (Bregs) within the tumour microenvironment (TME) is poorly understood, hindering their therapeutic exploitation. We addressed this gap by integrating single-cell transcriptomics with spatial localisation and in vitro assays to explore B cell functions in RCC. By taking advantage of a newly developed computational pipeline that projects cancer-specific clusters into a shared latent space, followed by validation in an RCC-specific dataset, we revealed a significant enrichment of regulatory CD19+CD27-IgD⁻CD21+CD11c⁻ double negative 1 (DN1) B cells in RCC compared to other cancer types and matched background tissues. DN1 B cell abundance correlated with shortened survival and risk of recurrence in RCC patients, offering their potential as a prognostic biomarker. Spatially, DN1 Bregs were localised to the peripheral regions of immature tertiary lymphoid structures, closely associated with IL-10+ and TGFβ+CD8+ T cells, suggesting a potential role in converting cytotoxic T cells to an immune-regulatory phenotype. We identified significant upregulation of the nucleic acid-sensing TLR7 and TLR9 signalling pathways in DN1 B cells, alongside increased expression of necrosis-associated genes in RCC. Stimulation with R848 or CpGC further enhanced DN1 Bregs' production of IL-10, TGFβ, and PD-L1, suppressing cytotoxic IFNγ+CD8+ T cells, an effect reversed by TGFβ inhibition. These findings suggest that tumour cell death releases RNA and DNA motifs, activating DN1 B cells and promoting their expansion and immunosuppressive role within the TME. Targeting and/or depleting DN1 Bregs offers a promising therapeutic strategy to enhance the efficacy of existing immunotherapies by promoting anti-tumourigenic B cell and T cell profiles.

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