Retinoid agonist Am80-enhanced neutrophil bactericidal activity arising from granulopoiesis in vitro and in a neutropenic mouse model

Despite advances in the therapeutic use of recombinant granulocyte colony-stimulating factor (G-CSF) to promote granulopoiesis of human hematopoietic stem cells (HSC), neutropenia remains one of the most serious complications of cancer chemotherapy. We discovered that retinoid agonist Am80 (tamibarotene) is more potent than G-CSF in coordinating neutrophil differentiation and immunity development. Am80-induced neutrophils (AIN) either in vitro or in neutropenic mouse model displayed strong bactericidal activities, similar to those of human peripheral blood neutrophils (PBN) or mouse peripheral blood neutrophils (MPBN) but markedly greater than did G-CSF-induced neutrophils (GIN). In contrast to GIN but similar to PBN, the enhanced bacterial killing by AIN accompanied both much better granule maturation and greater co-expression of CD66 antigen with the integrin β 2 subunit CD18. Consistently, anti-CD18 antibody neutralized Am80-induced bactericidal activities of AIN. These studies demonstrate that Am80 is more effective than G-CSF in promoting neutrophil differentiation and bactericidal activities, likely through coordinating the functional interaction of CD66 with CD18 to enhance the development of neutrophil immunity during granulopoiesis. Our findings herein suggest a molecular rationale for developing new therapy against neutropenia by using Am80 as a cost-effective treatment option.