Abstract / Summary
Abstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor outcomes. Although chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit in other cancers, their efficacy in AML has been limited by the lack of targets that can be safely engaged without causing myeloablation, and by an immunosuppressive tumor microenvironment. Leukocyte immunoglobulin-like receptor-B2 (LILRB2) has emerged as an immunosuppressive receptor, but its impact on CAR T-cell function and suitability as a therapeutic target remains unclear. We found that LILRB2 is expressed on AML blasts in 65% of patients, highly expressed on tumor-associated myeloid cells, and largely absent from healthy hematopoietic stem and progenitor cells. Knockout and overexpression models showed that LILRB2 impairs anti-CD33 directed CAR T-cell killing, expansion, and cytokine production, and increases exhaustion, effects which are partially reversible by antibody-mediated LILRB2 blockade. Transcriptomic analyses revealed suppression of immune-related pathways and induction of T‑cell senescence. Hence, we designed anti‑LILRB2 CAR T cells, which showed potent cytotoxicity in vitro and antitumor activity in vivo, including tumor eradication in xenograft models without detectable toxicity in humanized mice. Collectively, our results identify LILRB2 as a key regulator of CAR T-cell dysfunction and support LILRB2 targeting as a therapeutic strategy in AML.