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 6

Anti–CTLA-4 and anti–PD-1 do not interfere with the establishment of central B cell tolerance.

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Anti–CTLA-4 and anti–PD-1 do not interfere with the establishment of cen...
(A) Schematic diagram depicting the generation and injections of humanized mice. Fetal human CD34+ HSCs were injected i.v. into the adult NSG mice, along with surgical implantation of an autologous fetal thymic graft under the kidney capsule (NSG + thymus mouse model). After reconstitution, 100 μg of either anti–CTLA-4 or anti–PD-1 was injected intraperitoneally once a week for 5 weeks. (B) Representative pictures of the engrafted human thymic organoids of the indicated humanized mice. (C) Recombinant Abs cloned from single new emigrant/transitional B cells isolated from indicated humanized mouse were tested by ELISA for polyreactivity against dsDNA, insulin, and LPS reactivity. Dotted lines show the ED38 positive control. Horizontal lines show the cutoff OD405 for positive reactivity. For each mouse, frequencies of nonpolyreactive (white area) and polyreactive (black area) clones are summarized in a pie chart below, with the total number of clones tested indicated in the centers. The frequencies of polyreactive and antinuclear reactive new emigrant/transitional B cells are summarized in D and E, respectively. Each symbol represents the reactivity data for each humanized mouse determined from an average of n = 18 cloned recombinant antibodies. Averages are shown with a bar.