+A CAR T cell-amplified suppressive B cell circuit in AML
Year: 2026
Type: preprint
Abstract: Immunotherapy in acute myeloid leukemia (AML) is constrained by a hostile bone marrow niche. Here we identify atypical memory B cells (B atyp ) as a suppressive population within this microenvironment. Across single cell and flow cytometry cohorts, B atyp were expanded in AML, and their molecular and phenotypic profiles resembled those of atypical B cells associated with chronic inflammatory conditions. B atyp 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. B atyp suppressed T cell and CAR T cell responses via PD-1-and TGF-β-R signaling, and were enriched in non-responding patients with AML and myeloma. CD180-directed CAR T cells, targeting an antigen shared by B atyp 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 B atyp polarization, a constraint that can be relieved by dual blast- and B cell-targeting strategies.
Authors: Adrian Gottschlich, Vladyslav Kavaka, Thomas Alexander Janert, Veronika Igl, Emanuele Carlini, Lisa Rohrbacher, Wendy den Hartog, Jakob Harwood, Marcel P. Trefny, Selin Sogukcelik, Philipp Penovici, Bernhard Ransmayr, Christian Rausch, Franziska Brauneck, Stephanie Frenz-Wiessner, Isabel Goek, Gerulf Hänel, Cristina Zucchinetti, Arman Oner, Paula Sophie Zwicker, Ruth Grünmeier, Simon Delahais, Philipp Maximilian Schnell, Sayantan Nandi, Moritz Thomas, Ruben Brabenec, Daria Briukhovetska, Stefanos Michaelides, Rasmus David Müller, Lilli Ye Ballheimer, Christina Angeliki Tsiverioti, Gordon Victor Hoffmann, Sophia Stock, Ignazio Piseddu, Philipp Jie Müller, Moritz Kruppa, Walter Fiedler, Michael Rade, Markus Kreuz, Niklas Kehl, Anand S Bhagwat, Johannes Tobias Thiel, Dominik Steiner, Henrik Lauer, Adrien Daigeler, Christoph Klein, Carsten Marr, Stefan Endres, Kristin Reiche, Mirco Friedrich, Christine Bollwein, Stephan Ledderose, Martina Rudelius, Tobias Herold, Karsten Spiekermann, Maximilian Merz, Thorsten Mempel, Saar Gill, Marion Subklewe, Michael von Bergwelt-Baildon, Sebastian Kobold
Institutions: German Cancer Research Center, LMU Klinikum, Massachusetts General Hospital, Deutsches Konsortium für Translationale Krebsforschung, Mass General Brigham, Ludwig-Maximilians-Universität München, BG Klinik Tübingen, Institut für Klinische Neuroimmunologie, University of Tübingen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Universität Hamburg, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Helmholtz Munich, Technical University of Munich, Harvard University, Fraunhofer Institute for Cell Therapy and Immunology, University Hospital Heidelberg, Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Munich Center for Machine Learning, University Hospital Leipzig, Center for Scalable Data Analytics and Artificial Intelligence, Interdisciplinary Transformation University Austria, Broad Institute, Pathologisches Institut, München Klinik Bogenhausen, München Klinik, Memorial Sloan Kettering Cancer Center, German Center for Lung Research
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7222906804