Baseline memory B-cell enrichment and heightened B-cell activation are associated with irAEs

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 improve cancer outcomes but are frequently associated with breakdown of peripheral tolerance, triggering immune-related adverse events (irAEs). While T-cell mediated mechanisms have been extensively studied, the contribution of B cells in irAE pathogenesis remains underexplored. Here, we performed comprehensive phenotypic, functional, and signaling analyses of peripheral B cells in two independent ICI-treated patient cohorts: a melanoma cohort (PREDIMEL) and a pan-cancer cohort (AMICI). Before treatment initiation, patients who subsequently developed irAEs displayed enrichment of highly activated and differentiated B-cell subsets, including IgD⁻ memory B cells, activated memory B cells, and plasmablasts depending on cancer type. Beyond these phenotypic alterations, B cells from irAE-prone melanoma patients exhibited intrinsic functional dysregulation, characterized by enhanced BCR-induced signaling through Syk and PLCγ2 phosphorylation and increased antibody secretion upon stimulation. Despite inter-tumor and inter-cohort heterogeneity, irAE-associated B-cell subsets shared a common signature of increased activation and reduced inhibitory receptor expression. Together, these findings identify a pre-existing B-cell state with heightened activation potential and impaired regulation, revealing a functional B-cell predisposition that may contribute to immune toxicity following ICI therapy.