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 and André Veillette ()
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Jiaxin Li: Institut de recherches cliniques de Montréal (IRCM)
Zhaoyu Wang: Institut de recherches cliniques de Montréal (IRCM)
Xiaogan Qin: Institut de recherches cliniques de Montréal (IRCM)
Ming-Chao Zhong: Institut de recherches cliniques de Montréal (IRCM)
Zhenghai Tang: Institut de recherches cliniques de Montréal (IRCM)
Jin Qian: Institut de recherches cliniques de Montréal (IRCM)
Jiayu Dou: Institut de recherches cliniques de Montréal (IRCM)
Tracy Hussell: The University of Manchester
Philip D. King: University of Michigan Medical School
Jacques A. Nunès: Aix Marseille University
Yuji Yamanashi: The University of Tokyo
Dominique Davidson: Institut de recherches cliniques de Montréal (IRCM)
André Veillette: Institut de recherches cliniques de Montréal (IRCM)

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60456-3

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