The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors
The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors
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DOI：
10.1073/pnas.1121623109
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发表时间：
2012-04-24
影响因子：
11.1
通讯作者：
Weissman, Irving L.
中科院分区：
文献类型：
--
作者：
Willingham, Stephen B.;Volkmer, Jens-Peter;Weissman, Irving L.
CD47是一种吞噬细胞的信号，表达在所有人类实体瘤细胞的表面。对患者肿瘤和配对的邻近正常(非肿瘤)组织的分析表明，CD47在癌细胞上过度表达。CD47mRNA的表达水平与多种癌症类型的生存概率降低相关。CD47是SIRPα的配体，SIRPα是一种表达在巨噬细胞和树突状细胞上的蛋白质。在体外，使用靶向的单抗阻断CD47信号能够使巨噬细胞吞噬原本受到保护的肿瘤细胞。在用患者肿瘤细胞建立的原位免疫缺陷小鼠异种移植模型中，给予抗CD47抗体抑制了肿瘤的生长，并随着时间的推移增加了小鼠的存活率。在较大的肿瘤上开始抗CD47抗体治疗可以抑制肿瘤生长并预防或治疗转移，但在较小的肿瘤上开始治疗可能是治愈的。靶向CD47的安全性和有效性在免疫活性宿主中使用原位小鼠乳腺癌模型进行了进一步的测试和验证。这些结果表明，所有人类实体瘤细胞都需要CD47的表达来抑制吞噬细胞的天然免疫监视和消除。这些数据与其他人类肿瘤的类似发现表明，CD47是所有癌症上普遍表达的分子，其阻断吞噬功能是已知的，阻断其功能会导致肿瘤细胞的吞噬和消除。因此，CD47是癌症治疗的有效靶点。
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 formultiple types of cancer. CD47 is a ligand for SIRP alpha, 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.