Monocytes engineered with iSNAP inhibit human B-lymphoma progression.
Monocytes engineered with iSNAP inhibit human B-lymphoma progression.
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DOI：
10.1002/btm2.10285
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发表时间：
2022-05
影响因子：
7.4
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中科院分区：
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单核细胞是维持先天性和适应性免疫系统内稳态的重要调节因子，据报道在癌症进展中发挥重要作用。CD47 - SIRPα识别是一种抑制单核细胞和巨噬细胞吞噬作用的共抑制性免疫信号，通常被称为“不要吃我”信号。通过使用一种整合传感和激活蛋白（iSNAPs）的方法，我们重新连接了CD47 - SIRPα轴以创建iSNAP - M，它能激活工程化人类单核细胞（iSNAP - MC）中的通路。单核细胞/巨噬细胞标志物CD11b、CD14和CD31的mRNA表达水平在iSNAP单核细胞（iSNAP - MC）中上调。经佛波酯（PMA）诱导，iSNAP - MC衍生的巨噬细胞（iSNAP - MΦ）显示CD86和CD80上调，但CD206不上调。iSNAP - MΦ中肿瘤坏死因子α（TNFα）的表达和分泌也增加。此外，将iSNAP - MC注射到患有人类B淋巴瘤肿瘤的小鼠体内可抑制肿瘤进展。因此，通过重新连接CD47 - SIRPα轴阻断共抑制性免疫信号，工程化单核细胞可应用于癌症免疫治疗以抑制目标肿瘤。
Monocytes are important regulators for the maintenance of homeostasis in innate and adaptive immune system and have been reported to play important role in cancer progression. CD47‐SIRPα recognition is a coinhibitory immune signal to inhibit phagocytosis in monocytes and macrophages and has been well‐known as the “Don't eat me” signal. By using an approach of integrated sensing and activating proteins (iSNAPs), we have rewired the CD47‐SIRPα axis to create iSNAP‐M which activates pathways in engineered human monocytes (iSNAP‐MC). The mRNA expression levels of the monocyte/macrophage markers CD11b, CD14, and CD31 are upregulated in iSNAP‐monocytes (iSNAP‐MC). With PMA induction, the iSNAP‐MC‐derived macrophages (iSNAP‐MΦ) showed upregelation in CD86 and CD80, but not CD206. TNFα expression and secretion were also increased in iSNAP‐MΦ. Furthermore, the injection of iSNAP‐MC into mice bearing human B‐lymphoma tumors led to the suppression of tumor progression. Therefore, the engineered monocytes, via blockage of coinhibitory immune signals by rewiring CD47‐SIRPα axis, can be applied to suppress target tumors for cancer immunotherapy.