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

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.