SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis.
SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis.
复制标题
SHP2 deneddylation 通过 CD47/SIRPα 轴介导结肠癌的肿瘤免疫抑制
DOI：
10.1172/jci162870
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发表时间：
2023-02-15
影响因子：
15.9
通讯作者：
Ke, Yuehai
中科院分区：
文献类型：
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作者：
Li, Yiqing;Zhou, Hui;Liu, Pan;Lv, Dandan;Shi, Yichun;Tang, Bufu;Xu, Jiaqi;Zhong, Tingting;Xu, Wangting;Zhang, Jie;Zhou, Jianying;Ying, Kejing;Zhao, Yongchao;Sun, Yi;Jiang, Zhinong;Cheng, Hongqiang;Zhang, Xue;Ke, Yuehai
巨噬细胞表面的SIPRα与CD 47结合以抵抗前吞噬信号，但SIPRα下游信号如何控制肿瘤浸润性巨噬细胞（TIM）仍不清楚。在这里，我们报告，CD 47/信号调节蛋白α（SIRPα）轴需要酪氨酸磷酸酶SHP 2的去脱氧化。从机制上讲，含Src同源区2的蛋白酪氨酸磷酸酶2（SHP 2）在K358和K364位点上组成型neddylated;因此，其自抑制构象得以维持。作为对CD 47配体的SIRPα的响应，SHP 2被sentrin特异性蛋白酶8（SENP 8）去涡化，这导致吞噬杯处相关底物的去磷酸化和随后的巨噬细胞吞噬作用的抑制。此外，neddylation使骨髓-SHP 2失活，并大大提高了结直肠癌（CRC）免疫治疗的疗效。重要的是，我们观察到补充SHP 2变构抑制剂使免疫治疗抵抗性CRC对免疫治疗敏感。我们的结果强调了对免疫治疗无反应的CRC亚型依赖于SIRPα hiSHP 2 hiNEDD 8lo TIM，并强调了进一步探索CRC治疗中SHP 2靶向策略的必要性。
SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, Src homology region 2–containing protein tyrosine phosphatase 2 (SHP2) was constitutively neddylated on K358 and K364 sites; thus, its autoinhibited conformation was maintained. In response to CD47-liganded SIRPα, SHP2 was deneddylated by sentrin-specific protease 8 (SENP8), which led to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that supplementation with SHP2 allosteric inhibitors sensitized immune treatment–resistant CRC to immunotherapy. Our results emphasize that the CRC subtype that is unresponsive to immunotherapy relies on SIRPαhiSHP2hiNEDD8lo TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy.