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

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 R. Rausch; Franziska Brauneck; Stephanie Frenz-Wiessner; Isabel Goek; Gerulf Haenel; Cristina Zucchinetti; Arman Öner; Paula Zwicker; Ruth Gruenmeier; Simon Delahais; Philipp Maximilian Schnell; Sayantan Nandi; Moritz Thomas; Ruben Brabenec; Daria Briukhovetska; Stefanos Michaelides; Rasmus David Mueller; Lilli Ye Ballheimer

doi:10.64898/2026.10.12.758644

ImmunologybioRxivOct 21, 2026

Preprint

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

Adrian Gottschlich iD, Vladyslav Kavaka iD, Thomas Alexander Janert iD, Veronika Igl iD, Emanuele Carlini iD, Lisa Rohrbacher iD, Wendy den Hartog iD, Jakob Harwood, Marcel P. Trefny iD, Selin Sogukcelik, Philipp Penovici, Bernhard Ransmayr iD, Christian R. Rausch iD, Franziska Brauneck iD, Stephanie Frenz-Wiessner iD, Isabel Goek, Gerulf Haenel, Cristina Zucchinetti iD, Arman Öner iD, Paula Zwicker iD, Ruth Gruenmeier, Simon Delahais iD, Philipp Maximilian Schnell, Sayantan Nandi, Moritz Thomas iD, , Sebastian Kobold iD

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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