CTLA-4 blockade shifts the B cell repertoire toward autoimmunity

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Abstract

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.

Authors

Elif Çakan, Meng Wang, Yile Dai, Adrien Mirouse, Clarence Rachel Villanueva-Pachas, Delphine Bouis, Joshua M. Boeckers, Ruchi Gera, Sally Yraita, Leslie Clapp, Ana Luisa Perdigoto, Fabien R. Delmotte, Christopher Massad, Antonietta Bacchiocchi, Aaron M. Ring, Yuval Kluger, Harriet M. Kluger, Kevan C. Herold, Eric Meffre