Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity

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Cazaux, Marine | Grandjean, Capucine | Lemaître, Fabrice | Garcia, Zacarias | Beck, Richard | Milo, Idan | Postat, Jérémy | Beltman, Joost | Cheadle, Eleanor | Bousso, Philippe

Edité par CCSD ; Rockefeller University Press -

International audience. CAR T cells represent a potentially curative strategy for B cell malignancies. However, the outcome and dynamics of CAR T cell interactions in distinct anatomical sites are poorly understood. Using intravital imaging, we tracked interactions established by anti-CD19 CAR T cells in B cell lymphoma-bearing mice. Circulating targets trapped CAR T cells in the lungs, reducing their access to lymphoid organs. In the bone marrow, tumor apoptosis was largely due to CAR T cells that engaged, killed, and detached from their targets within 25 min. Notably, not all CAR T cell contacts elicited calcium signaling or killing while interacting with tumors, uncovering extensive functional heterogeneity. Mathematical modeling revealed that direct killing was sufficient for tumor regression. Finally, antigen-loss variants emerged in the bone marrow, but not in lymph nodes, where CAR T cell cytotoxic activity was reduced. Our results identify a previously unappreciated level of diversity in the outcomes of CAR T cell interactions in vivo, with important clinical implications.

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