Arbe-Barnes, E. H. | Search bioRxiv

bioRxiv2025

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

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.

immunology↗

bioRxiv2020

Immune responses in pancreatic cancer may be restricted byprevalence of activated regulatory T-cells, dysfunctionalCD8+ T-cells, and senescent T-cells

Pancreatic cancer has the worst prognosis of any human malignancy and leukocyte infiltration is a major prognostic marker of the disease. As current immunotherapies confer negligible survival benefits, there is a need to better characterise leukocytes in pancreatic cancer to identify better therapeutic strategies. In this study, we analysed 32 human pancreatic cancer patients from two independent cohorts. A multi-parameter mass-cytometry analysis was performed on 32,000 T-cells from eight patients. Single-cell RNA sequencing dataset analysis was performed on a cohort of 24 patients. Multiplex immunohistochemistry imaging and spatial analysis were performed to map immune infiltration into the tumour microenvironment. Regulatory T-cell populations demonstrated highly immunosuppressive states with high TIGIT, ICOS and CD39 expression. CD8+ T-cells were found to be either in senescence or an exhausted state. The exhausted CD8 T-cells had low PD-1 expression but high TIGIT and CD39 expression. These findings were corroborated in an independent pancreatic cancer single-cell RNA dataset from additional 24 patients. These data suggest that T-cells are major players in the suppressive microenvironment of pancreatic cancer. Our work identifies novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.

immunology↗