SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin.
SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin.
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SLAMF7对于通过MAC-1整合素对造血肿瘤细胞的吞噬作用至关重要。
DOI：
10.1038/nature22076
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发表时间：
2017-04-27
期刊：
影响因子：
64.8
通讯作者：
Veillette A
中科院分区：
文献类型：
--
作者：
Chen J;Zhong MC;Guo H;Davidson D;Mishel S;Lu Y;Rhee I;Pérez-Quintero LA;Zhang S;Cruz-Munoz ME;Wu N;Vinh DC;Sinha M;Calderon V;Lowell CA;Danska JS;Veillette A
癌细胞通过多种机制逃避抗肿瘤免疫，包括上调抑制性免疫检查点受体的配体表达。巨噬细胞的吞噬作用在癌症控制中起关键作用。治疗性阻断信号调节蛋白（SIRP）-α（巨噬细胞上的抑制性受体）或其在肿瘤细胞上表达的配体CD 47可改善体外和体内肿瘤细胞消除，表明阻断SIRPα-CD 47检查点可用于治疗人类癌症。然而，负责肿瘤细胞吞噬作用的前噬细胞受体在很大程度上是未知的。我们发现，与非造血肿瘤细胞相比，巨噬细胞对SIRPα-CD 47阻断的应答更有效地吞噬造血肿瘤细胞。使用缺乏同型造血细胞特异性受体的信号淋巴细胞活化分子（SLAM）家族的小鼠，我们确定了SIRPα-CD 47阻断期间造血肿瘤细胞的吞噬作用在体外和体内严格依赖于SLAM家族受体。在小鼠和人类细胞中，这种功能需要单个SLAM家族成员SLAMF 7（也称为CRACC，CS 1，CD 319），表达在巨噬细胞和肿瘤细胞靶点上。与大多数SLAM受体功能相反，SLAMF 7介导的吞噬作用不依赖于信号淋巴细胞活化分子相关蛋白（SAP）衔接子。相反，它依赖于SLAMF 7与整合素Mac-1相互作用的能力，并利用涉及免疫受体酪氨酸激活基序的信号。这些发现阐明了巨噬细胞吞噬和破坏造血肿瘤细胞的机制。它们还揭示了SLAM受体的新型SAP衔接子独立功能。最后，他们表明，表达SLAMF 7的肿瘤患者更有可能对SIRPα-CD 47阻断治疗有反应。
Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα–CD47 checkpoint could be useful in treating human cancer. However, the prophagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα–CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα–CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα–CD47 blockade therapy.
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影响因子：
11.8
作者：
Heit, Bryan;Kim, Hani;Cosio, Gabriela;Castano, Diana;Collins, Richard;Lowell, Clifford A.;Kain, Kevin C.;Trimble, William S.;Grinstein, Sergio
通讯作者：
Grinstein, Sergio
影响因子：
30.5
作者：
Cruz-Munoz, Mario-Ernesto;Dong, Zhongjun;Veillette, Andre
通讯作者：
Veillette, Andre
DOI：
10.1084/jem.20160552
发表时间：
2016-09-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guo H;Cranert SA;Lu Y;Zhong MC;Zhang S;Chen J;Li R;Mahl SE;Wu N;Davidson D;Waggoner SN;Veillette A
通讯作者：
Veillette A
影响因子：
8.7
作者：
Hamerman JA;Ni M;Killebrew JR;Chu CL;Lowell CA
通讯作者：
Lowell CA
影响因子：
8.7
作者：
Gordon S;Plüddemann A;Martinez Estrada F
通讯作者：
Martinez Estrada F