CTLA-4 blockade shifts the B cell repertoire toward autoimmunity

Checkpoint inhibitors targeting CTLA-4 and PD-1 revolutionized the treatment of cancer patients, but their use is limited by the emergence of immune-related adverse events (irAEs). We assessed autoreactive B cell frequencies in the blood of cancer patients before and after treatment with checkpoint inhibitors by testing the reactivity of recombinant antibodies cloned from single B cells. We found that anti-PD-1 and anti-CTLA-4 combination therapy induced the emergence of autoreactive mature naive B cells, whereas central B cell tolerance remained functional. In contrast, anti-PD-1 alone did not alter autoreactive B cell counterselection. Anti-CTLA-4 injections in humanized mice also resulted in the production of autoreactive B cells, whereas anti-PD-1 did not. We conclude that CTLA-4 but not PD-1 is required for the removal of developing autoreactive mature naive B cells and that CTLA-4 blockade broadens the peripheral B cell repertoire, which likely contains clones that promote not only irAEs but also antitumor responses.