Abstract
Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by inflammatory lesions arising from the anomalous accumulation of pathogenic CD1a(+) CD207(+) dendritic cells (DCs). SIRPα is a transmembrane protein highly expressed in myeloid cells such as DCs and macrophages. Here we show that SIRPα is a potential therapeutic target for LCH. We found that SIRPα is expressed in CD1a(+) cells of human LCH lesions as well as in CD11c(+) DCs in the spleen, liver, and lung of a mouse model of LCH (BRAFV600E(CD11c) mouse), in which an LCH-associated active form of human BRAF is expressed in a manner dependent on the mouse Cd11c promoter. BRAFV600E(CD11c) mice manifested markedly increased numbers of CD4(+) T cells, regulatory T cells, and macrophages as well as of CD11c(+) MHCII(+) DCs in the spleen. Monotherapy with a mAb to SIRPα greatly reduced the percentage of CD11c(+) MHCII(+) DCs in peripheral blood, LCH-like lesion size in the liver, and the number of CD11c(+) MHCII(+) DCs in the spleen of the mutant mice. Moreover, this mAb promoted macrophage-mediated phagocytosis of CD11c(+) DCs from BRAFV600E(CD11c) mice, whereas it had no effects on the viability or CCL19-dependent migration of such CD11c(+) DCs or on their expression of the chemokine genes Ccl5, Ccl20, Cxcl11, and Cxcl12. Our results thus suggest that anti-SIRPα monotherapy is a promising approach to the treatment of LCH that is dependent in part on the promotion of the macrophage-mediated killing of LCH cells.