CD84: un Nuovo Target per la Terapia a cellule CAR-T nelle Leucemie Acute Pediatriche

ABSTRACT Immunotherapy, including chimeric antigen receptor T (CAR-T) cell therapy, has profoundly transformed the treatment of relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia in children and adults. However, similar advances have not yet been achieved in other hematologic malignancies. In particular, children with R/R acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL) continue to face limited therapeutic options, largely due to the scarcity of leukemia-specific surface antigens that could be safely targeted. In an effort to contribute addressing this unmet clinical need we identified a novel and potentially actionable immunotherapeutic target, CD84, characterized by a distinctive expression profile in pediatric leukemias. CD84 that our group identified via a gene expression analysis performed on a large sample cohort, was here evaluated for expression in 339 pediatric patients affected with AML, ALL or other myeloid neoplasms by flow cytometry. At diagnosis, pediatric AML blasts displayed high and remarkably consistent CD84 expression, with nearly 90% of cases classified as positive according to WHO criteria. CD84 antigen density on leukemic blasts was significantly higher than on not-neoplastic lymphocytes and monocyte–myeloid cells, and remained stable across genetic subgroups, at disease relapse, and in follow-up samples. Interestingly, higher CD84 expression at diagnosis was associated with subsequent disease relapse, suggesting that CD84 overexpression may be linked to more aggressive leukemia phenotypes, potentially by supporting the survival and persistence of leukemia-initiating or stem cell populations (LIC/LSC) or other biologically aggressive subclones. Elevated CD84 expression was also observed in other subgroups such as Down syndrome–associated AML and therapy-related AML. In lymphoid leukemias, CD84 expression was more heterogeneous; nevertheless, a distinct subset of T-ALL cases showed increased CD84 expression on leukemic blasts. Importantly, the analysis of healthy bone marrow samples showed very low to null CD84 expression on hematopoietic stem and early progenitor cells, that showed expression levels significantly lower than those of leukemic blasts. Overall, these findings identify CD84 as a robust and broadly expressed antigen in pediatric AML and selected subgroups of T-ALL, supporting its exploitation in the ongoing translational studies evaluating it as a candidate target for CAR-T cell–based immunotherapy.