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.
Avoiding phagocytosis by tumor-associated macrophages is required for the growth and metastasis of solid tumors (1). Accumulating evidence suggests that cell-surface expression of CD47 is a common mechanism by which cells protect themselves from phagocytosis (1). CD47 expression is required to protect transfused red blood cells, platelets, and lymphocytes from rapid elimination by splenic macrophages (2⇓–4). Mobilized hematopoietic stem cells protect themselves from phagocytosis by increasing CD47 expression as they pass through phagocyte-lined sinusoids and decrease it after relocating to marrow niches (5). Moreover, CD47 expression levels predicted the probability that hematopoietic stem cells would be phagocytosed while circulating (5).
CD47 is a widely expressed transmembrane protein with numerous functions (6). CD47 functions as a ligand for signal regulatory protein-α (SIRPα), a protein expressed on macrophages and dendritic cells (7). Upon binding CD47, SIRPα initiates a signaling cascade that results in the inhibition of phagocytosis (6). This “don't eat me” signal is transmitted by phosphorylation of the immunoreceptor tyrosine-based inhibition motifs present on the cytoplasmic tail of SIRPα (8). Subsequent binding and activation of SHP-1 and SHP-2 [src homology-2 (SH2)-domain containing protein tyrosine phosphatases] blocks phagocytosis, potentially by preventing the accumulation of myosin-IIA at the phagocytic synapse (9–12).
Scientists now show that CD47 is expressed on all human patient cancer cells tested. It appears that CD47 is a unique non-housekeeping cell-surface marker expressed by all human cancers. Increased CD47 mRNA expression levels in some solid tumors correlated with a decreased probability of patient survival. Monoclonal antibodies targeted to CD47 enabled the phagocytosis of patient solid tumor cells in vitro, inhibited the growth of orthotopically xenotransplanted human patient tumors, and prevented the metastasis of human patient tumor cells. These results establish CD47 as a critical regulator of innate immune surveillance.