Tumor-infiltrating CD27-IgD- regulatory B cells suppress cytotoxic CD8+T cell responses in renal cell carcinoma

Baig, Z.; Withnell, I.; Ng, J. C. F.; Piper, C. J. M.; Bradford, H. F.; Rullan, A.; Arbe-Barnes, E. H.; de Brito, C. G. X.; Di Tullio, A.; Mitchell, T. J.; Stauss, H. J.; Tran, M. G. B.; Fraternali, F.; Mauri, C.

doi:10.1101/2025.07.08.663720

bioRxiv · 10.1101/2025.07.08.663720

Tumor-infiltrating CD27-IgD- regulatory B cells suppress cytotoxic CD8+T cell responses in renal cell carcinoma

Baig, Z.·Withnell, I.·Ng, J. C. F.·Piper, C. J. M.·Bradford, H. F.·Rullan, A.·Arbe-Barnes, E. H.·de Brito, C. G. X.·Di Tullio, A.·Mitchell, T. J.·Stauss, H. J.·Tran, M. G. B.·Fraternali, F.·Mauri, C.

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Abstract

B cells play a pivotal role in shaping the tumor microenvironment (TME) and tertiary lymphoid structures (TLS), but the functions of specific B cell subsets in cancer pathogenesis remain unclear. Using a novel tissue-centric single cell RNA-sequencing (scRNA-seq) bioinformatic workflow aimed at unraveling cancer-specific clusters, combined with flow cytometry and high-plex spatial imaging, we identify a renal cell carcinoma (RCC)-specific enrichment of CD27-IgD-CD21+CD11c- double negative 1 (DN1) B cells associated with worse prognosis and regulatory function. Spatial profiling localizes DN1 Bregs within immature TLSs, in close proximity to IL-10 and TGF{beta}CD8T cells. RCC-resident DN1 B cells are enriched for endosomal Toll-like receptor (TLR) signaling pathways and stimulation of tumor-infiltrating lymphocytes (TILs) with TLR agonists induces the differentiation of IL-10+ and TGF{beta}+DN Bregs suppressing CD8+T cell cytotoxicity, partially via IL-10 and TGF{beta}. These findings identify a pro-tumorigenic B cell population with potential diagnostic and therapeutic relevance in RCC.

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Baig, Z., Withnell, I., Ng, J. C. F., Piper, C. J. M., Bradford, H. F., Rullan, A., Arbe-Barnes, E. H., de Brito, C. G. X., Di Tullio, A., Mitchell, T. J., Stauss, H. J., Tran, M. G. B., Fraternali, F., Mauri, C.. 2025-07-12. Tumor-infiltrating CD27-IgD- regulatory B cells suppress cytotoxic CD8+T cell responses in renal cell carcinoma. https://doi.org/10.1101/2025.07.08.663720

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