Pan-cancer single-cell and spatial transcriptomics analyses delineate response-associated heterogeneity and therapeutic targets of tumor-infiltrating B cells following immune checkpoint blockade.

Tumor-infiltrating B cells (TIBs) are emerging as central regulators of anti-tumor immunity, but their biological functions, spatial niches, and cross talk with tumor-infiltrating lymphocytes vary widely across cancer types, particularly with regard to cancer immunotherapies. Yet a pan-cancer atlas linking their transcriptional profile to the immune checkpoint blockade (ICB) response has been missing. Here, we presented the pan-cancer ICB response B cell atlas, constructed from 688 single-cell transcriptomes (24 cancer types, 241,645 cells). Twenty-four B cell subsets were identified, and their proportion dynamics and transcriptomic features across cancers were revealed. B cell subsets proportion-based NMF analyses identified 5 TIME subtypes in which TIME-Plasma and TIME-Memory showing repressed apoptosis, higher antigen presentation, and enrichment in responders were correlated with better survival in several cancers. Pseudo-time trajectories delineated two conserved differentiation pathways that branch at the memory B cell node and showed distinct correlations with B cell apoptosis and ICB response. Pan-cancer spatial deconvolution showed that several responder-derived B cell subsets including plasma cells, memory B cells, and activated B cells were more co-occurred compared to non-responder-derived B cell subsets. Utilizing pan-cancer TCGA datasets, the clinical heterogeneity of B cell subsets from distinct response groups was revealed. We constructed a pan-cancer ICB response Geneformer model and in silico perturbed all genes. Thirteen candidate genes, which were significantly correlated with the B cell ICB response state transition, were identified. Overall, our study illuminates the heterogeneity of TIBs and improves our understanding of cancer-specific B cell subsets within the context of tumor immunotherapies.