B cells and the therapeutic index of checkpoint blockade

Combined CTLA-4 and PD-1 blockade is effective in treating melanoma and additional cancers but frequently causes immune-related adverse events (irAEs). irAEs cause treatment disruption and discontinuation and remain difficult to manage clinically. In this issue, Dhodapkar and colleagues assessed data from a small randomized clinical trial testing rituximab-mediated B cell depletion in combined CTLA-4/PD-1 blockade–treated patients with advanced melanoma. Despite premature discontinuation of the trial due to a high rate of rituximab hypersensitivity, they report that preemptive B cell depletion was associated with fewer severe toxicities without evident loss of antitumor activity. These findings raise broader questions about the organization of checkpoint-induced autoimmunity, the emerging concept of immune reset, and the compartment-specific roles of B cells in antitumor immunity.