Targeting BCL11B in chimeric antigen receptor-engineered lymphoid progenitors propagates adaptive NK-like cell responses against leukemia

Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B propagates CAR-induced killer (CARiK) cell development. Here, we show that CRISPR-mediated BCL11B knockout (ko) in early lymphoid progenitors distinctively modulates this process depending on its use alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated either innate or adaptive anti-leukemic immune responses. With CAR expression being a prerequisite for antigen-specific CARiK responses, additional BCL11B ko was critical for the acquisition of adaptive killer cell functions such as clonal expansion, persistence, and recall responses. These findings have important insights on how BCL11B targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells. Transcriptional profiling of in vivo matured lymphoid progenitor cells transduced with an inducible CD123 CAR and Bcl11b-targeted sgRNA by scRNA sequencing analysis