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

Acute myeloid leukemia (AML) is a malignancy that faces limitations due to an unfavorable bone marrow microenvironment. Researchers have now identified a distinct population of memory B cells (Batyp) that play a role in suppressing the immune response within this niche. Across various single-cell and flow cytometry studies, Batyp were found to be more prevalent in AML patients, and their characteristics mirrored those of atypical B cells linked to chronic inflammation.

The researchers discovered that these Batyp cells adapted within the AML environment, and their growth was boosted by CAR T cell targeting of the AML cells.

The scientists found that the polarization of Batyp cells was regulated by Toll-like receptor, interferon, and CD70-CD27 pathways. These specialized Batyp cells curtailed both T cell and CAR T cell reactions through PD-1 and TGF-beta signaling. Moreover, Batyp cells were more common in AML and myeloma patients who did not respond well to treatment.

The researchers found that targeting an antigen shared by Batyp and AML cells with CD180-directed CAR T cells could resist the suppressive effects of Batyp in laboratory settings and eradicate the disease in B cell-humanized xenografts, all while leaving hematopoietic stem cells untouched. Importantly, the CAR T cells were able to reinforce their own suppressive niche by promoting the growth of Batyp cells, a factor that could potentially impede the effectiveness of CAR T cell therapy.

The researchers suggested that a dual strategy targeting both blasts and Batyp cells could help overcome this constraint.