title: CD47-signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction.
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.
authors: Sanquin Research and Landsteiner Laboratory, Academic Medical Center,  University of Amsterdam, 1066 CX Amsterdam,  The Netherlands.
authors: Xi Wen
authors: XW
authors: Zhao
authors: Ellen M
authors: EM
authors: van Beek
authors: Karin
authors: K
authors: Schornagel
authors: Hans
authors: H
authors: Van der Maaden
authors: Michel
authors: M
authors: Van Houdt
authors: Marielle A
authors: MA
authors: Otten
authors: Pascal
authors: P
authors: Finetti
authors: Marjolein
authors: M
authors: Van Egmond
authors: Takashi
authors: T
authors: Matozaki
authors: Georg
authors: G
authors: Kraal
authors: Daniel
authors: D
authors: Birnbaum
authors: Andrea
authors: A
authors: van Elsas
authors: Taco W
authors: TW
authors: Kuijpers
authors: Francois
authors: F
authors: Bertucci
authors: Timo K
authors: TK
authors: van den Berg
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051928:CD47 Antigen; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D000068878:Trastuzumab