Department of Neurosurgery and.
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Clin Invest. 2023 Feb 15;133(4):e167894. doi: 10.1172/JCI167894.
The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors.
CD47/信号调节蛋白α（SIRPα）轴作为一种抑制吞噬作用的检查点，也是癌症免疫逃逸的关键介质。许多癌症，包括结直肠癌（CRC），利用 CD47 的表达逃避吞噬清除并激活先天免疫系统。先前的工作表明，不同的翻译后修饰模式介导 CD47/SIRPα 轴的调节机制。在本期 JCI 中，Li 等人表明，泛素样修饰物 neddylation 使 Src 同源区域 2 含蛋白酪氨酸磷酸酶 2（SHP2）失活，该通路的下游靶标。他们进一步表明，抑制 SHP2 可使 CRC 细胞对先前耐药的免疫疗法敏感。总的来说，这些结果强调了在 CRC 及可能其他免疫治疗耐药肿瘤中同时靶向 SHP2 和免疫检查点（例如程序性死亡 1 [PD1]）的必要性。
