A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer
A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer
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DOI：
10.1038/s41551-018-0254-6
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发表时间：
2018-08-01
影响因子：
28.1
通讯作者：
Sengupta, Shiladitya
中科院分区：
文献类型：
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作者：
Kulkarni, Ashish;Chandrasekar, Vineethkrishna;Sengupta, Shiladitya
有效地激活能够“吞噬”癌细胞的巨噬细胞是一项具有挑战性的工作。特别是，癌细胞分泌巨噬细胞集落刺激因子(MCSF)，使肿瘤相关的巨噬细胞从抗肿瘤的M1表型分化为促肿瘤的M2表型。此外，癌细胞可以表达CD47，CD47是一种与巨噬细胞上的信号调节蛋白α(SIRPα)受体连接的信号，以防止吞噬。在这里，我们表明，由抑制集落刺激因子1受体(CSF-1R)的两亲分子组成的超分子组件和显示药物与抗体比率为17,000的SIRPα阻断抗体可以使这两种机制失效。这种超分子结合在巨噬细胞上的SIRPα上，阻断CD47-SIRPα信号轴，同时持续抑制CSF-1R。该超分子增强了肿瘤微环境中M2到M1的复极化，并显著提高了在两种侵袭性黑色素瘤和乳腺癌动物模型中的抗肿瘤和抗转移效率，这是关于临床上可用的小分子和CSF-1R信号生物抑制剂。同时阻断CD47-SIRPα和MCSF-CSF-1R信号轴可能构成一种有前途的免疫治疗方法。
Effectively activating macrophages that can 'eat' cancer cells is challenging. In particular, cancer cells secrete macrophage colony stimulating factor (MCSF), which polarizes tumour-associated macrophages from an antitumour M1 phenotype to a pro-tumorigenic M2 phenotype. Also, cancer cells can express CD47, a 'don't eat me' signal that ligates with the signal regulatory protein alpha (SIRP alpha) receptor on macrophages to prevent phagocytosis. Here, we show that a supramolecular assembly consisting of amphiphiles inhibiting the colony stimulating factor 1 receptor (CSF-1R) and displaying SIRP alpha-blocking antibodies with a drug-to-antibody ratio of 17,000 can disable both mechanisms. The supramolecule homes onto SIRP alpha on macrophages, blocking the CD47-SIRP alpha signalling axis while sustainedly inhibiting CSF-1R. The supramolecule enhances M2-to-M1 repolarization within the tumour microenvironment, and significantly improves antitumour and antimetastatic efficacies in two aggressive animal models of melanoma and breast cancer, with respect to clinically available small-molecule and biologic inhibitors of CSF-1R signalling. Simultaneously blocking the CD47-SIRP alpha and MCSF-CSF-1R signalling axes may constitute a promising immunotherapy.