The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer
The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer
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DOI：
10.1038/s41392-020-0124-z
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发表时间：
2020-04-15
影响因子：
39.3
通讯作者：
Yu, Songtao
中科院分区：
文献类型：
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作者：
Wang, Xiaojiao;Luo, Xi;Yu, Songtao
抑制性受体信号调节蛋白-α (Sirp α) 是一种骨髓特异性免疫检查点，可与肿瘤和正常组织细胞上表达的“别吃我”信号 CD47 结合。然而，Sirpα在肿瘤相关巨噬细胞（TAM）中表达的概况和调控机制仍不清楚。在这里，我们发现 TAM 中 Sirp α 的表达随着结直肠癌 (CRC) 的进展而动态增加。从机制上讲，CRC 细胞来源的乳酸诱导 TAM 中转录因子 Ap-2 α 从细胞质发生核转位。 Ap-2 α 通过与小鼠 Elk-1 启动子中位于 -1396/-1391 的保守元件 GCCTGC 结合而发挥 Elk-1 转录因子的作用。随后，Elk-1蛋白与小鼠Sirp α启动子中的两个保守位点CTTCCTACA（位于-229/-221）和CTTCCTCTC（位于-190/-182）结合，并促进TAM中Sirp α的表达。从功能上讲，巨噬细胞特异性敲除 Ap-2 α 显着促进 TAM 的吞噬活性并抑制 CRC 进展，而这些效应被 Elk-1 的转基因巨噬细胞特异性表达所阻止，Elk-1 以 Sirp α 依赖性方式调节 TAM 吞噬作用和 CRC 发展。此外，我们发现 TAM 中 Elk-1 的表达与 Sirp α 的表达呈正相关，并且与 CRC 患者的不良生存率相关。总而言之，我们的研究结果揭示了结直肠癌逃避先天免疫监视的新机制，并为结直肠癌患者基于巨噬细胞的免疫治疗提供了潜在靶标。
The inhibitory receptor signal regulatory protein-alpha (Sirp alpha) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47, which is expressed on tumor and normal tissue cells. However, the profile and regulatory mechanism of Sirp alpha expression in tumor-associated macrophages (TAMs) are still not clear. Here, we found that the expression of Sirp alpha in TAMs increased dynamically with colorectal cancer (CRC) progression. Mechanistically, CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2 alpha from the cytoplasm in TAMs. Ap-2 alpha functioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at -1396/-1391 in the mouse Elk-1 promoter. Subsequently, the Elk-1 protein bound to two conserved sites, CTTCCTACA (located at -229/-221) and CTTCCTCTC (located at -190/-182), in the mouse Sirp alpha promoter and promoted Sirp alpha expression in TAMs. Functionally, the macrophage-specific knockout of Ap-2 alpha notably promoted the phagocytic activity of TAMs and suppressed CRC progression, whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1, which regulated TAM phagocytosis and CRC development in a Sirp alpha-dependent manner. Furthermore, we showed that Elk-1 expression was positively correlated with Sirp alpha expression in TAMs and was associated with poor survival in CRC patients. Taken together, our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.