Fig. 8: A schematic demonstrating Breg dynamics and suppressive mechanisms between toxicity and non-toxicity patients.

This schematic illustrates the interplay between Bregs, CD4 + T cells, Tfh and Tfr cells and the role of suppressive cytokines and the PD-1-PD-L1 axis in mediating downstream responses. Bregs can be PD-1 or PDL1-positive. Interactions with tumour cell PD-L1 (1) or upon encountering PD-L1 + cells, this PD-1 triggering results in the acquisition of suppressive functions with tumour-specific T-cell immunity and promotes cancer growth via IL-10 production. Interaction with CD4 + specific PD-1 via B-cell-specific PD-L1 (2) inhibits Tfh maturation and differentiation from CD4 + T cells and subsequent entry into the germinal centre where Tfh help induces B-cell maturation into memory and terminally differentiated plasma cells. These direct PD-1-PD-L1 interactions between CD4 + and Breg cells, respectively, result in Stat5 upregulation and subsequent Tfh suppression. CXCR5 + CD25 + Foxp3 + T follicular regulatory cells work synergistically with Breg cells to skew the balance away from Tfh maturation and expansion. Tfh suppression also occurs via suppressive cytokine signalling (3). These three mechanisms are thought to be the B-cell-exerted brakes on autoimmunity which prevents unregulated immune-related adverse events following checkpoint blockade.