CTLA-4 blockade shifts the B cell repertoire toward autoimmunity
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
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
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Research Article Autoimmunity Immunology

CTLA-4 blockade shifts the B cell repertoire toward autoimmunity

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

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Figure 7

Anti–CTLA-4 injections induce an accumulation of autoreactive mature naive B cells.

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Anti–CTLA-4 injections induce an accumulation of autoreactive mature nai...
Recombinant Abs cloned from single mature naive B cells isolated from the indicated humanized mice were tested by ELISA for anti–HEp-2 cell reactivity (A) and for polyreactivity defined by anti-dsDNA, anti-insulin, and anti-LPS multireactivity (C). Dotted lines show the ED38 positive control. Horizontal lines show the cutoff OD405 for positive reactivity. For each humanized mouse, the frequency of nonreactive (white area) and reactive (black area) clones is summarized in a pie chart below, with the total number of clones tested indicated in the centers. The frequencies of HEp-2–reactive, polyreactive, and antinuclear-reactive mature naive B cells are summarized in B, D, and E. Each symbol represents a humanized mouse, and each data point was obtained from an average of n = 23 cloned recombinant antibodies. Averages are shown with a bar, and P values were determined by paired Student’s t test. *P < 0.05, **P < 0.01, ****P < 0.0001. (F) Representative nuclear staining patterns for recombinant antibodies cloned from single mature naive B cells.