A CAR T cell-amplified suppressive B cell circuit in AML
- 1Department of Medicine III, LMU University Hospital, LMU Medizin, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany; Institute of Clinical Pharmacology,
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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BibTeX
@misc{gottschlich2026cellamplified,
title = {{A CAR T cell-amplified suppressive B cell circuit in AML}},
author = {A. Gottschlich and V. Kavaka and T. A. Janert and V. Igl and E. Carlini and L. Rohrbacher and W. den Hartog and J. Harwood and M. P. Trefny and S. Sogukcelik and P. Penovici and B. Ransmayr and C. Rausch and F. Brauneck and S. Frenz-Wiessner and I. Goek and G. Haenel and C. Zucchinetti and A. Oner and P. S. Zwicker and R. Gruenmeier and S. Delahais and P. M. Schnell and S. Nandi and M. Thomas and R. Brabenec and D. Briukhovetska and S. Michaelides and R. D. Mueller and L. Y. Ballheimer and C. A. Tsiverioti and G. V. Hoffmann and S. Stock and I. Piseddu and P. J. Mueller and M. Kruppa and W. Fiedler and M. Rade and M. Kreuz and N. Kehl and A. S. Bhagwat and J. T. Thiel and Ste},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.758644},
url = {https://www.biorxiv.org/content/10.64898/2026.10.12.758644v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A CAR T cell-amplified suppressive B cell circuit in AML
AU - A. Gottschlich
AU - V. Kavaka
AU - T. A. Janert
AU - V. Igl
AU - E. Carlini
AU - L. Rohrbacher
AU - W. den Hartog
AU - J. Harwood
AU - M. P. Trefny
AU - S. Sogukcelik
AU - P. Penovici
AU - B. Ransmayr
AU - C. Rausch
AU - F. Brauneck
AU - S. Frenz-Wiessner
AU - I. Goek
AU - G. Haenel
AU - C. Zucchinetti
AU - A. Oner
AU - P. S. Zwicker
AU - R. Gruenmeier
AU - S. Delahais
AU - P. M. Schnell
AU - S. Nandi
AU - M. Thomas
AU - R. Brabenec
AU - D. Briukhovetska
AU - S. Michaelides
AU - R. D. Mueller
AU - L. Y. Ballheimer
AU - C. A. Tsiverioti
AU - G. V. Hoffmann
AU - S. Stock
AU - I. Piseddu
AU - P. J. Mueller
AU - M. Kruppa
AU - W. Fiedler
AU - M. Rade
AU - M. Kreuz
AU - N. Kehl
AU - A. S. Bhagwat
AU - J. T. Thiel
AU - Ste
PY - 2026
DA - 2026/10/12
PB - bioRxiv
DO - 10.64898/2026.10.12.758644
UR - https://www.biorxiv.org/content/10.64898/2026.10.12.758644v1
AB - 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.
ER -