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SLAMF3 and SLAMF4 are immune checkpoints that constrain macrophage phagocytosis of hematopoietic tumors
Dan Li1, Wei Xiong1, Yuande Wang1
1School of Medicine and Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China.
Abstract:
The interaction of SIRPα with CD47 represents a major mechanism for preventing macrophage phagocytosis. However, CD47-independent mechanisms are poorly defined. Here, we report a critical role of SLAM family receptors (SFRs), ubiquitously expressed on hematopoietic cells and forming homotypic interactions, in constraining macrophage phagocytosis. We found that SFR deficiency triggered macrophage phagocytosis of hematopoietic cells, leading to severe rejection of donor hematopoietic graft in recipient mice. Specific SFR members, mainly SLAMF3 and SLAMF4, were identified as "don't eat me" receptors on macrophages. These receptors inhibited "eat me" signals, such as LRP1-mediated activation of mTOR and Syk, through SH2 domain-containing phosphatases. SFRs combined with, but were independent of, CD47 to mitigate macrophage phagocytosis, and the combined deletion of SFRs and CD47 resulted in hematopoietic cytopenia in mice. This SFR-mediated tolerance was compromised in patients with hemophagocytic lymphohistiocytosis, a syndrome characterized by inappropriate phagocytosis toward hematopoietic cells. Loss of SFRs potently elicited macrophage rejection of hematopoietic tumors. Deletion of SFRs also significantly enhanced the phagocytosis of CD19-positive hematopoietic targets by the macrophages expressing the chimeric CD19 antigen receptor. Therefore, SFR-mediated inhibition of macrophage phagocytosis is critical to hematopoietic homeostasis, and SFRs may represent previously unknown targets for tumor immunotherapy.
Insights
SLAM family receptors (SFRs) prevent macrophages from engulfing hematopoietic cells, crucial for immune tolerance. Loss of SFRs causes graft rejection and may offer new cancer immunotherapy targets.
Area of Science:
- Immunology
- Cell Biology
- Hematology
Background:
- The CD47-SIRPα axis is a known 'don't eat me' signal inhibiting macrophage phagocytosis.
- CD47-independent mechanisms controlling macrophage phagocytosis of hematopoietic cells remain poorly understood.
Purpose of the Study:
- To investigate the role of SLAM family receptors (SFRs) in regulating macrophage phagocytosis of hematopoietic cells.
- To identify novel 'don't eat me' signals beyond the CD47 pathway.
Main Methods:
- Utilized mouse models with SFR deficiencies to assess hematopoietic graft rejection.
- Employed in vitro assays to analyze macrophage phagocytosis of hematopoietic cells.
- Investigated the molecular mechanisms involving phosphatases, mTOR, and Syk signaling pathways.
- Analyzed patient samples from hemophagocytic lymphohistiocytosis cases.
Main Results:
- SFR deficiency led to increased macrophage phagocytosis of hematopoietic cells and severe graft rejection.
- SLAMF3 and SLAMF4 were identified as key SFRs acting as 'don't eat me' receptors.
- SFRs inhibit 'eat me' signals via SH2 domain-containing phosphatases, independent of CD47.
- Combined deletion of SFRs and CD47 caused hematopoietic cytopenia.
- SFR-mediated tolerance was impaired in hemophagocytic lymphohistiocytosis patients.
- Loss of SFRs enhanced macrophage rejection of tumors and chimeric antigen-targeted cells.
Conclusions:
- SFRs play a critical role in maintaining hematopoietic homeostasis by inhibiting macrophage phagocytosis.
- SFRs represent a novel, CD47-independent pathway for immune tolerance.
- SFRs are potential therapeutic targets for enhancing anti-tumor immunity and treating disorders of inappropriate phagocytosis.
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