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 · 29 citations
Immunology and Microbiology · #Phagocytosis and Immune Regulation #Immunotherapy and Immune Responses #Complement system in diseases

paper · doi:10.1073/pnas.1106550108

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

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• Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. [europepmc]
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• 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]
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• Functions of Thrombospondin-1 in the Tumor Microenvironment. [europepmc]
• Roles of tumor-associated macrophages in tumor progression: implications on therapeutic strategies. [europepmc]
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• Exploiting innate immunity for cancer immunotherapy. [europepmc]

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