Abstract 3322: SIRPα is a potential therapeutic target for Langerhans cell histiocytosis
Authors: Okamoto Takeshi , Murata Yoji , Hazama Daisuke , Sakamoto Mariko , Kakuchi Yuka , Saito Yasuyuki , Kotani Takenori , Maniwa Yoshimasa , Matozaki Takashi 
Published: September 2020

Abstract
Langerhans cell histiocytosis (LCH) is a rare disease, in which immature dendritic cells (DCs) with the same traits as Langerhans cells proliferate and develop various symptoms at various sites such as the skin, bone, lungs, and pituitary. Most patients with LCH are thought to have abnormalities in the mitogen-activated protein (MAP) kinase pathway, with more than 50% of BRAF mutations. It is rarely associated with morbidity and mortality in patients with single organ disease, but sometimes fatal in patients with multiple organ disease, and there is still no effective treatment for these patients. SIRPα is a transmembrane protein with three immunoglobulin-like domains in the extracellular region. This protein is especially abundant in myeloid cells such as DCs and macrophages. SIRPα interacts with its ligand CD47, another transmembrane protein, and we and others previously showed that the CD47-SIRPα interaction negatively regulates the phagocytosis by macrophages of target cells. We also showed that anti-SIRPα antibodies could promote the killing by macrophages of SIRPα-expressing tumor cells through dual mechanisms: direct induction of the antibody-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. By the use of tissue sections from patients with LCH, here we showed that DCs positive for CD1a, a definitive diagnostic marker in LCH, expressed high levels of SIRPα, and inflammatory cells significantly infiltrated around such CD1a+ DCs in LCH regions. As a mouse model for LCH, BRAFV600ECD11c mice, in which BRAFV600E were expressed under the control of the CD11c promoter, displayed a severe LCH-like disease phenotype with a short lifespan and the increased infiltration of CD11c+ DCs into multiple organs. Among CD11c+ DCs, the number of SIRPα+ DCs (SIRPα+/CD11c+) increased in the spleen, liver, and lung. Moreover, an anti-SIRPα antibody that blocks the CD47-SIRPα interaction stimulated the phagocytosis by bone marrow-derived macrophages of CD11c+ DCs sorted from the spleen of BRAFV600ECD11c in vitro. Given the prominent expression of SIRPα in CD11c+ DCs from BRAFV600ECD11c mice, anti-SIRPα antibodies likely promote the phagocytosis of these cells by macrophages through above-mentioned dual mechanisms. In conclusion, we have first demonstrated that CD1a+ DCs in LCH regions expressed high levels of SIRPα. Moreover, it is also suggested that the anti-SIRPα antibody is a potential tool for the new therapy of LCH.
Citation Format: Takeshi Okamoto, Yoji Murata, Daisuke Hazama, Mariko Sakamoto, Yuka Kakuchi, Yasuyuki Saito, Takenori Kotani, Yoshimasa Maniwa, Takashi Matozaki. SIRPα is a potential therapeutic target for Langerhans cell histiocytosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3322.