Blocking the CD47-SIRPα interaction reverses the disease phenotype in a polycythemia vera mouse model

Lysenko, Veronika; Schürch, Patrick M.; Tuzlak, Selma; Wijk, Nicole Wildner-Verhey van; Kovtonyuk, Larisa V.; Manz, Markus G.; Kreutmair, Stefanie; Theocharides, Alexandre

doi:10.1038/s41375-023-01903-2

Cited by 4 publications

(2 citation statements)

References 41 publications

(51 reference statements)

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“…Under physiological conditions, CD47 participates in various biological processes and reduces excessive destruction of cells and cellular components, including red blood cells (RBCs), 152 – 154 platelets, 155 and neuronal synapses. 156 – 158 Under pathological conditions, phagocytosis is abnormally attenuated through the CD47-SIRPα axis and mediates retention of pathological RBCs, 159 , 160 macrophage dysfunction, 161 , 162 and abnormal proliferation of brain tissue. 163 Regarding anti-tumor immunity, CD47 is expressed in various hematological and solid tumors, 164 – 167 promoting tumor survival by evading the phagocytic activity of innate immune cells, laying the foundation for blocking the CD47-SIRPα axis to enhance tumor cell killing by phagocytosis.…”

Section: Inhibitory Checkpoints and Protein Familiesmentioning

confidence: 99%

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Yin,

Li,

Zhang

et al. 2024

Sig Transduct Target Ther

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Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

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Section: Inhibitory Checkpoints and Protein Familiesmentioning

confidence: 99%

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Yin,

Li,

Zhang

et al. 2024

Sig Transduct Target Ther

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“…The binding of CD47 on erythrocyte to the SIRPα on macrophages prevented erythrocyte phagocytosis by suppressing phagocytic activity. The polycythemia phenotype was restored by intercepting CD47-SIRPα through either anti-CD47 treatment or loss of the inhibitory SIRPα-signal in a PV mouse model ( 12 ). Both solid and hematologic malignancies expressed higher levels of CD47, which bound with SIRPα to protect the tumor cell against macrophage-mediated phagocytosis ( 13 – 15 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of CD47 expression on CD14+ monocytes by interferon-α in PBC patients

Su,

Jin,

Liu

et al. 2023

Front. Immunol.

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BackgroundPrimary biliary cholangitis (PBC) is a chronic intrahepatic cholestatic autoimmune liver disease characterized by inflammatory injury of small and medium-sized bile ducts in the liver. The pathogenesis of PBC has yet to be entirely understood. CD47/signal-regulatory protein alpha (SIRPα) is closely related to developing autoimmune diseases by promoting inflammatory response. However, the effect of CD47/SIRPα on inflammatory response in PBC patients is still unclear.ObjectiveWe investigated the expression of CD47/SIRPα and the effect of inflammatory cytokines on the CD47 expression, analyzed potential autoantibodies against CD47 and the effect of anti-CD47 antibody on the inflammatory response in PBC, provided laboratory basis for the study of the pathogenesis and targets for non-invasive diagnosis and treatment on PBC.MethodsThe expression levels of CD47 and SIRPα on peripheral blood mononuclear cells (PBMC) were measured in 14 patients with PBC (the PBC group) and 13 healthy subjects (the Control group) by flow cytometry (FCM). The PBMC derived from healthy subjects were stimulated with healthy subjects’ serum, PBC patients’ serum, IFN-α or TNF-α, and the CD47 expression level on CD14+ monocytes was detected by FCM. The level of serum anti-CD47 antibody or IFN-α in PBC patients and healthy subjects was analyzed by ELISA. FCM was used to examine the TNF-α expression level in CD14+ monocytes of healthy subjects stimulated with isotype control antibody, anti-CD47 antibody, LPS or LPS combined with CD47 antibody.ResultsThe CD47 expression level on the CD14+ monocytes in PBC patients was statistically higher than that in the Control group (P<0.01). Compared with the Control group (PBMC+healthy serum), the CD47 expression on CD14+ monocyte stimulated with the PBC patients’ serum (PBMC+PBC patients’ serum) was increased (P<0.001); the CD47 expression on CD14+ monocyte stimulated with IFN-α (PBMC + IFN-α) increased gradually with the increased concentration of IFN-α (P<0.05). However, there was no similar trend on CD14+ monocyte stimulated with the TNF-α (PBMC+TNF-α) (P>0.05). The levels of serum anti-CD47 antibody and IFN-α in the PBC patients were higher than those in healthy subjects (P<0.05). The TNF-α expression level in CD14+ monocyte stimulated with the LPS (PBMC+LPS) or anti-CD47 antibody+LPS group (PBMC+LPS+anti-CD47 antibody) was significantly increased than that in the Control group (PBMC+isotype control antibody) (P<0.01 and P<0.001, respectively). The TNF-α expression level in CD14+ monocyte stimulated with the anti-CD47 antibody + LPS was higher than that with the LPS (P< 0.05).ConclusionThe CD47 may be related to the pathogenesis of PBC by inflammatory response. The CD47/SIRPα signal were imbalanced in PBC patients. The presence of serum anti-CD47 antibodies in PBC patients provides a laboratory basis for clinical diagnosis and treatment.

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CpG and Rutin Co‐Loaded DNA Tetrahedra for Targeted Therapy of Intracerebral Hemorrhage: Synergistic Hematoma Clearance and Neuroinflammation Inhibition

Wang,

Xie,

et al. 2024

Adv Funct Materials

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Intracerebral hemorrhage (ICH) presents a formidable challenge due to its high mortality and disability rates, primarily attributed to cerebral hematoma formation and ensuing neuroinflammation. Swift hematoma removal is paramount for prognosis, yet existing interventions carry risks and limitations. Notably, elevated CD47 expression on hematoma‐associated RBC triggers a “don't eat me” signal, impeding hematoma clearance, while microglial/macrophage erythrophagocytosis exacerbates oxidative stress and the RBC lysate evokes neuroinflammation. To address this conundrum, a multifunctional nanomedicine (TD‐CFR), employing DNA tetrahedra (TD) as a carrier for ICH treatment is introduced. The investigations reveal that CpG enhances the phagocytosis of CD47‐expressing RBC by microglia/macrophages via lipid metabolism modulation. Integration of CpG into TD preserves its pro‐phagocytic efficacy, while TD's double‐stranded region enables efficient encapsulation of Rutin, a potent anti‐inflammatory and antioxidant flavonoid. Capitalizing on disrupted blood‐brain barrier integrity at the hemorrhage site, TD‐CFR achieves robust enrichment within cerebral hematoma post‐intravenous administration, augmented by folate receptor‐mediated targeting of microglia/macrophages. Efficacy assessments in mouse and rabbit ICH models confirm TD‐CFR's therapeutic benefits, including hematoma clearance, neuroinflammation suppression, and brain function restoration. Leveraging TD's high biosafety profile and dual active ingredient loading capacity, the study unveils a promising drug treatment paradigm for ICH.

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Blocking the CD47-SIRPα interaction reverses the disease phenotype in a polycythemia vera mouse model

Cited by 4 publications

References 41 publications

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Regulation of CD47 expression on CD14+ monocytes by interferon-α in PBC patients

CpG and Rutin Co‐Loaded DNA Tetrahedra for Targeted Therapy of Intracerebral Hemorrhage: Synergistic Hematoma Clearance and Neuroinflammation Inhibition

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