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CD47-signal regulatory protein-? (SIRP?) 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-? (SIRP?) on myeloid cells. Mice that lack the SIRP? cytoplasmic tail, and hence its inhibitory signaling, display increased antibody-mediated elimination of melanoma cells in vivo. Moreover, interference with CD47-SIRP? interactions by CD47 knockdown or by antagonistic antibodies against CD47 or SIRP? 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-SIRP? interactions participate in a homeostatic mechanism that restricts antibody-mediated killing of tumor cells. This provides a rational basis for targeting CD47-SIRP? interactions, using for instance the antagonistic antibodies against human SIRP? described herein, to potentiate the clinical effects of cancer therapeutic antibodies.

SUBMITTER: Zhao XW 

PROVIDER: S-EPMC3215076 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Zhao Xi Wen XW   van Beek Ellen M EM   Schornagel Karin K   Van der Maaden Hans H   Van Houdt Michel M   Otten Marielle A MA   Finetti Pascal P   Van Egmond Marjolein M   Matozaki Takashi T   Kraal Georg G   Birnbaum Daniel D   van Elsas Andrea A   Kuijpers Taco W TW   Bertucci Francois F   van den Berg Timo K TK  

Proceedings of the National Academy of Sciences of the United States of America 20111031 45


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  ...[more]

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