CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth
Jiaxin Li, Zhaoyu Wang, Xiaogan Qin, Ming‐Chao Zhong, Zhenghai Tang, Jin Qian, Jiayu Dou, Tracy Hussell, Philip D. King, Jacques A. Nunès, Yuji Yamanashi, Dominique Davidson, André Veillette
Abstract
Targeting macrophage inhibitory receptors like signal regulatory protein α (SIRPα) is a promising avenue in cancer treatment. Whereas the ligand of SIRPα, CD47, is widely expressed on tumor cells, its simultaneous presence on all normal cells raises concerns about toxicity and efficacy. This study identifies CD200R1, which binds CD200 on specific tumor types and limited normal cells, as an alternative inhibitory checkpoint for phagocytosis. Blocking or removing CD200R1 from macrophages or CD200 from tumor cells increases phagocytosis and suppresses tumor growth. In humans, CD200R1 is mainly expressed in immunosuppressive macrophages and is induced by interleukin-4. Unlike SIRPα that utilizes phosphatases Src homology 2 domain phosphatase (SHP)−1 and SHP-2, CD200R1 mediates its inhibitory effect via the kinase Csk. Combined CD200R1-CD200 and SIRPα-CD47 blockade further boosts phagocytosis and reduces tumor growth of CD200-expressing tumors, compared to either blockade alone. Thus, targeting CD200R1-CD200 is a promising strategy for immune checkpoint blockade in macrophages, either alone or alongside blockade of other checkpoints. CD200R1 is a transmembrane receptor expressed on macrophages. Here the authors report that the interaction of CD200R1 with its ligand CD200, expressed by tumor cells, suppresses phagocytosis, and that targeting CD200R1-CD200 promotes macrophage-mediated anti-tumor response.