2. Academic Validation
  3. CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth

CD200R1-CD200 checkpoint inhibits phagocytosis differently from SIRPα-CD47 to suppress tumor growth

  • Nat Commun. 2025 Jun 3;16(1):5145. doi: 10.1038/s41467-025-60456-3.
Jiaxin Li 1 2,  Zhaoyu Wang 1 2,  Xiaogan Qin 1 2,  Ming-Chao Zhong 1,  Zhenghai Tang 1,  Jin Qian 1,  Jiayu Dou 1 2,  Tracy Hussell 3 4,  Philip D King 5,  Jacques A Nunès 6,  Yuji Yamanashi 7,  Dominique Davidson 1,  André Veillette 8 9 10
Affiliations

Affiliations

  • 1 Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada.
  • 2 Department of Medicine, McGill University, Montréal, QC, Canada.
  • 3 Lydia Becker Institute for Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK.
  • 4 Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • 5 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 6 Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm, CNRS, Aix Marseille University, Marseille, France.
  • 7 Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 8 Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada. andre.veillette@ircm.qc.ca.
  • 9 Department of Medicine, McGill University, Montréal, QC, Canada. andre.veillette@ircm.qc.ca.
  • 10 Department of Medicine, University of Montréal, Montréal, Québec, Canada. andre.veillette@ircm.qc.ca.
PMID: 40461553 DOI: 10.1038/s41467-025-60456-3
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.

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