| First Author | Zhao XW | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 45 | Pages | 18342-7 |
| PubMed ID | 22042861 | Mgi Jnum | J:180227 |
| Mgi Id | MGI:5305878 | Doi | 10.1073/pnas.1106550108 |
| Citation | Zhao XW, et al. (2011) CD47-signal regulatory protein-alpha (SIRPalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A 108(45):18342-7 |
| abstractText | 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-alpha (SIRPalpha) on myeloid cells. Mice that lack the SIRPalpha cytoplasmic tail, and hence its inhibitory signaling, display increased antibody-mediated elimination of melanoma cells in vivo. Moreover, interference with CD47-SIRPalpha interactions by CD47 knockdown or by antagonistic antibodies against CD47 or SIRPalpha 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-SIRPalpha interactions participate in a homeostatic mechanism that restricts antibody-mediated killing of tumor cells. This provides a rational basis for targeting CD47-SIRPalpha interactions, using for instance the antagonistic antibodies against human SIRPalpha described herein, to potentiate the clinical effects of cancer therapeutic antibodies. |
