Combination immune checkpoint blockade with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) leads to higher response rates in patients with melanoma than either single agent alone. Yet, a drawback of this combination is an increase in immune-related adverse events. Until now attention has focused on T cell-mediated immune responses following immune checkpoint therapy, and the role B cells might play has been relatively unexplored. Das et al. found a decrease in circulating B cells and an increase in CD21lo B cells and plasmablasts following inhibition of CTLA4 and PD1 in patients. The CD21lo B cells were associated with greater clonality, activation and PD1 expression. Importantly, these early B cell changes occurred before and correlated with both the number and timing of treatment-related toxicities. Thus, detection of B cells could serve as a predictive biomarker of patients at increased risk of developing autoimmunity.