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.
10.1101/2025.07.08.663720 bioRxivShow 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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