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Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis

Okamoto, Takeshi Murata, Yoji Hasegawa, Daiichiro Yoshida, Makiko Tanaka, Daisuke Ueda, Takashi Hazama, Daisuke Oduori, Okechi S. Komori, Satomi Takai, Tomoko Saito, Yasuyuki Kotani, Takenori Kosaka, Yoshiyuki Maniwa, Yoshimasa Matozaki, Takashi 神戸大学

2023.05

概要

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 (BRAFV600ECD11c mouse), in which an LCH-associated active form of human BRAF is expressed in a manner dependent on the mouse Cd11c promoter. BRAFV600ECD11c 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 BRAFV600ECD11c 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.

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S U P P O R T I N G I N FO R M AT I O N

Additional supporting information can be found online in the

Supporting Information section at the end of this article.

How to cite this article: Okamoto T, Murata Y, Hasegawa D,

et al. Targeting of SIRPα as a potential therapy for

Langerhans cell histiocytosis. Cancer Sci. 2023;114:18711881. doi:10.1111/cas.15758

13497006, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cas.15758 by Kobe University, Wiley Online Library on [08/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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OKAMOTO et al.

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