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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (45), p.18342-18347
Main Authors: Zhao, Xi Wen, van Beek, Ellen M, Schornagel, Karin, Van der Maaden, Hans, Van Houdt, Michel, Otten, Marielle A, Finetti, Pascal, Van Egmond, Marjolein, Matozaki, Takashi, Kraal, Georg, Birnbaum, Daniel, van Elsas, Andrea, Kuijpers, Taco W, Bertucci, Francois, van den Berg, Timo K
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Monoclonal, Humanized - pharmacology
Antibody dependent cell cytotoxicity
Antibody-Dependent Cell Cytotoxicity - drug effects
Antineoplastic Agents - pharmacology
Biological Sciences
Breast cancer
breast neoplasms
Cancer
CD47 Antigen - immunology
CD47 Antigen - metabolism
ErbB-2 protein
Female
Flow Cytometry
Life Sciences
Mammary Neoplasms, Experimental - immunology
Mammary Neoplasms, Experimental - metabolism
Mammary Neoplasms, Experimental - pathology
Medical treatment
Melanoma
Mice
Mice, Inbred C57BL
Monoclonal antibodies
Myeloid cells
Neutrophils
patients
Phagocytes
Receptors
Receptors, Immunologic - immunology
Receptors, Immunologic - metabolism
Signal regulatory protein- alpha
Signal Transduction
therapeutics
Trastuzumab
Tumor cells
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1106550108