Immunotherapy Breakthrough: Targeting CD200R1 to Overcome Resistant Blood Cancers

CD200R1-CD200: A Novel Macrophage Checkpoint

On June 3, 2025, André Veillette’s team at the Montreal Clinical Research Institute (IRCM) published a groundbreaking study in Nature Communications, revealing the CD200R1-CD200 axis as a macrophage immune checkpoint with potential for treating CD200-positive cancers, such as chronic lymphocytic leukemia and multiple myeloma. The study also highlighted synergy with SIRPα-CD47 blockade, amplifying anti-tumor effects.

CD200R1, a transmembrane receptor expressed on macrophages, T cells, and certain myeloid cells, binds to CD200, which is overexpressed in tumors like B-cell malignancies, melanoma, and lung cancer but minimally present in normal cells. The team hypothesized that targeting CD200R1-CD200 could offer a highly specific therapeutic approach and explored its role in macrophage phagocytosis.

Using mass spectrometry, the team analyzed CD11b in mouse bone marrow-derived macrophages (BMDMs), uncovering a physical association between CD200R1 and CD11b, suggesting direct regulation of phagocytosis.

Fig. 1. Physical association between CD200R1 and CD11b in macrophages.

 

To validate this, antibodies were used to block CD200 or CD200R1, testing their impact on phagocytosis of CD200-positive tumor cell lines (WEHI-231, A20, J558, TUBO). Blocking CD200R1-CD200 significantly enhanced macrophage phagocytosis, with actin polarization increasing within 15 minutes, indicating a direct inhibitory effect.

Fig. 2. Enhanced macrophage phagocytosis following CD200R1-CD200 blockade.

 

The study also confirmed CD200R1-CD200’s regulation of multiple pro-phagocytic receptors, enhancing IgG-opsonized WEHI-231 cell phagocytosis (Fc receptor-dependent), non-opsonized J558 cell phagocytosis (SLAMF7-dependent), and complement C3bi-triggered CD11b-mediated phagocytosis.

Fig. 3 Regulation of pro-phagocytic receptors by CD200R1-CD200.

 

Gene knockout experiments further validated these findings, showing enhanced phagocytosis in CD200R1-deficient macrophages or CD200-deficient WEHI-231 cells, confirming the axis as a key phagocytosis inhibitor.

In Vivo Anti-Tumor Efficacy

In RAG-1 knockout mice (lacking T and B cells to isolate macrophage effects), the team tested CD200R1-CD200 blockade by implanting WEHI-231 (liver tumors) and A20 (subcutaneous tumors) cells and treating with CD200 antibodies plus IgG-opsonizing antibodies. CD200 blockade significantly reduced tumor volume, weight, and immune cell infiltration, extending survival. Macrophage depletion abolished these effects, proving macrophage dependency.

Fig. 4 In vivo anti-tumor effects of CD200 blockade.

 

Combining CD200R1-CD200 and SIRPα-CD47 blockade proved more effective than either alone, significantly boosting phagocytosis and anti-tumor efficacy, highlighting the potential of dual-checkpoint inhibition.

Human Relevance

Analysis of human macrophages revealed low CD200R1 expression in unactivated monocyte-derived macrophages but significant upregulation in IL-4-induced M2 macrophages, common in tumor microenvironments, underscoring CD200R1’s role in immune suppression. CD200’s high expression in human B-cell malignancies and solid tumors like melanoma and lung cancer, coupled with poor prognosis, supports its therapeutic potential.

Fig. 5 CD200R1 expression in human M2 macrophages. 

abinScience Research Tools

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