The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors
2012
Willingham, Stephen B. | Volkmer, Jens-Peter | Gentles, Andrew J. | Sahoo, Debashis | Dalerba, Piero | Mitra, Siddhartha S. | Wang, Jian | Contreras-Trujillo, Humberto | Martin, Robin | Cohen, J. D. (Justin D.) | Lovelace, Patricia | Scheeren, Ferenc A. | Chao, Mark P. | Weiskopf, Kipp | Tang, Chad | Volkmer, Anne Kathrin | Naik, Tejaswitha J. | Storm, Theresa A. | Mosley, Adriane R. | Edris, Badreddin | Schmid, Seraina M. | Sun, Chris K. | Chua, Mei-Sze | Murillo, Oihana | Rajendran, Pradeep | Cha, Adriel C. | Chin, Robert K. | Kim, Dongkyoon | Adorno, Maddalena | Raveh, Tal | Tseng, Diane | Jaiswal, Siddhartha | Enger, Per Øyvind | Steinberg, Gary K. | Li, Gordon | So, Samuel K. | Majeti, Ravindra | Harsh, Griffith R. | Rijn, Matt van de | Teng, Nelson N. H. | Sunwoo, John B. | Alizadeh, Ash A. | Clarke, Michael F. | Weissman, Irving L.
CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
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