CD47–signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction

2011/10/31 by Xi Zhao, Xi Wen Zhao, Ellen M. van Beek +17 · 274 citations
Immunology and Microbiology · #Antibody #Biology #Breast cancer #CD47 #Cancer #Cancer cell #Cancer research #Complement system in diseases #Immune system #Immunology #Immunotherapy and Immune Responses #Monoclonal antibody #Phagocytosis and Immune Regulation #SKBR3 #Trastuzumab

paper · doi:10.1073/pnas.1106550108

published in Proceedings of the National Academy of Sciences 108(45), 18342-18347 (National Academy of Sciences)

openalex publication_date 2011/10/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/26

Abstract

Monoclonal antibodies are among the most promising therapeutic agents for treating cancer. Therapeutic cancer antibodies bind to tumor cells, turning them into targets for immune-mediated destruction. We show here that this antibody-mediated killing of tumor cells is limited by a mechanism involving the interaction between tumor cell-expressed CD47 and the inhibitory receptor signal regulatory protein-α (SIRPα) on myeloid cells. Mice that lack the SIRPα cytoplasmic tail, and hence its inhibitory signaling, display increased antibody-mediated elimination of melanoma cells in vivo. Moreover, interference with CD47-SIRPα interactions by CD47 knockdown or by antagonistic antibodies against CD47 or SIRPα significantly enhances the in vitro killing of trastuzumab-opsonized Her2/Neu-positive breast cancer cells by phagocytes. Finally, the response to trastuzumab therapy in breast cancer patients appears correlated to cancer cell CD47 expression. These findings demonstrate that CD47-SIRPα interactions participate in a homeostatic mechanism that restricts antibody-mediated killing of tumor cells. This provides a rational basis for targeting CD47-SIRPα interactions, using for instance the antagonistic antibodies against human SIRPα described herein, to potentiate the clinical effects of cancer therapeutic antibodies.

Citations

• Role of CD47 as a Marker of Self on Red Blood Cells

Cited by

• Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases
• Engineering Macrophages for Cancer Immunotherapy and Drug Delivery
• The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer
• Macrophage targeting in cancer
• The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. [europepmc]
• Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. [europepmc]
• CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. [europepmc]
• Macrophages are critical effectors of antibody therapies for cancer. [europepmc]
• Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. [europepmc]
• A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. [europepmc]
• Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 "Don't Eat Me" Signals. [europepmc]
• Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. [europepmc]
• Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo. [europepmc]
• CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. [europepmc]
• Anti-SIRP α antibodies as a potential new tool for cancer immunotherapy. [europepmc]
• Novel targeted therapies and immunotherapy for advanced thyroid cancers. [europepmc]
• ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. [europepmc]
• Glutaminyl cyclase is an enzymatic modifier of the CD47- SIRPα axis and a target for cancer immunotherapy. [europepmc]
• Phagocytosis checkpoints as new targets for cancer immunotherapy. [europepmc]
• WNT Signaling in Tumors: The Way to Evade Drugs and Immunity. [europepmc]
• Advances in Anti-Tumor Treatments Targeting the CD47/SIRPα Axis. [europepmc]
• Macrophage checkpoint blockade: results from initial clinical trials, binding analyses, and CD47-SIRPα structure-function. [europepmc]
• The CD47-SIRPα Immune Checkpoint. [europepmc]
• Dual blockade of CD47 and HER2 eliminates radioresistant breast cancer cells. [europepmc]
• CD47/SIRPα blocking peptide identification and synergistic effect with irradiation for cancer immunotherapy. [europepmc]
• Functions of Thrombospondin-1 in the Tumor Microenvironment. [europepmc]
• Roles of tumor-associated macrophages in tumor progression: implications on therapeutic strategies. [europepmc]
• Cancer immunotherapies: advances and bottlenecks. [europepmc]
• Exploiting innate immunity for cancer immunotherapy. [europepmc]

Related

• The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer
• CD47 inhibits phagocytosis through Vav dephosphorylation
• Retargeted adenoviruses for local IgA and CD47 blocker production as a novel cancer therapy
• Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47
• Galectin-3 Cooperates with CD47 to Suppress Phagocytosis and T-cell Immunity in Gastric Cancer Peritoneal Metastases