As previously reported, CD47 was also detected on dissociated normal (noncancer) cells ( Fig. CD47 was also highly expressed on tumor samples when analyzed by immunofluorescence ( Fig. 1 A for representative analyses, see Fig. CD47 expression was detected on nearly all cancer cells from every primary and xenograft patient tumor sample evaluated ( Fig. Viability dyes and antibodies targeted to CD45, CD31, and H-2K b/d were used to exclude dead, nontumor (lineage), and mouse cells. We evaluated CD47 expression on dissociated patient ovarian, breast, colon, bladder, glioblastoma, hepatocellular carcinoma, and prostate tumor cells by flow cytometry. CD47 is therefore a validated target for cancer therapies. 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. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination.
The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. 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. 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. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected.
CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47, a “don't eat me” signal for phagocytic cells, is expressed on the surface of all human solid tumor cells.
0 kommentar(er)
