A CAR T cell-amplified suppressive B cell circuit in AML

Gottschlich, A.; Kavaka, V.; Janert, T. A.; Igl, V.; Carlini, E.; Rohrbacher, L.; den Hartog, W.; Harwood, J.; Trefny, M. P.; Sogukcelik, S.; Penovici, P.; Ransmayr, B.; Rausch, C.; Brauneck, F.; Frenz-Wiessner, S.; Goek, I.; Haenel, G.; Zucchinetti, C.; Oner, A.; Zwicker, P. S.; Gruenmeier, R.; Delahais, S.; Schnell, P. M.; Nandi, S.; Thomas, M.; Brabenec, R.; Briukhovetska, D.; Michaelides, S.; Mueller, R. D.; Ballheimer, L. Y.; Tsiverioti, C. A.; Hoffmann, G. V.; Stock, S.; Piseddu, I.; Mueller, P. J.; Kruppa, M.; Fiedler, W.; Rade, M.; Kreuz, M.; Kehl, N.; Bhagwat, A. S.; Thiel, J. T.; Ste

doi:10.64898/2026.10.12.758644

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bioRxiv · 10.64898/2026.10.12.758644

A CAR T cell-amplified suppressive B cell circuit in AML

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Abstract

Immunotherapy in acute myeloid leukemia (AML) is constrained by a hostile bone marrow niche. Here we identify atypical memory B cells (Batyp) as a suppressive population within this microenvironment. Across single cell and flow cytometry cohorts, Batyp were expanded in AML, and their molecular and phenotypic profiles resembled those of atypical B cells associated with chronic inflammatory conditions. Batyp were polarized within the AML microenvironment, and this was amplified by CAR T cell-AML interactions. Mechanistically, polarization was dependent on Toll-like receptor, interferon and CD70-CD27 signaling. Batyp suppressed T cell and CAR T cell responses via PD-1- and TGF-beta signaling, and were enriched in non-responding patients with AML and myeloma. CD180-directed CAR T cells, targeting an antigen shared by Batyp and AML blasts, resisted suppression in vitro and cleared disease in B cell-humanized xenografts while sparing hematopoietic stem cells, with B cell engagement further enhancing their expansion. CAR T cells thus reinforce their own suppressive niche through Batyp polarization, a constraint that can be relieved by dual blast- and B cell-targeting strategies.

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Gottschlich, A., Kavaka, V., Janert, T. A., Igl, V., Carlini, E., Rohrbacher, L., den Hartog, W., Harwood, J., Trefny, M. P., Sogukcelik, S., Penovici, P., Ransmayr, B., Rausch, C., Brauneck, F., Frenz-Wiessner, S., Goek, I., Haenel, G., Zucchinetti, C., Oner, A., Zwicker, P. S., Gruenmeier, R., Delahais, S., Schnell, P. M., Nandi, S., Thomas, M., Brabenec, R., Briukhovetska, D., Michaelides, S., Mueller, R. D., Ballheimer, L. Y., Tsiverioti, C. A., Hoffmann, G. V., Stock, S., Piseddu, I., Mueller, P. J., Kruppa, M., Fiedler, W., Rade, M., Kreuz, M., Kehl, N., Bhagwat, A. S., Thiel, J. T., Ste. 2026-10-18. A CAR T cell-amplified suppressive B cell circuit in AML. https://doi.org/10.64898/2026.10.12.758644

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