Tianjin Key Laboratory of Cellular and Molecular Immunology, and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China; State Key Laboratory of Experimental Hematology, Tianjin, China; Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China.
Laboratory of Neuro-oncology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Cancer Lett. 2024 Jun 28;592:216934. doi: 10.1016/j.canlet.2024.216934. Epub 2024 May 4.
The Staphylococcal nuclease and Tudor domain containing 1 (SND1) has been identified as an oncoprotein. Our previous study demonstrated that SND1 impedes the major histocompatibility complex class I (MHC-I) assembly by hijacking the nascent heavy chain of MHC-I to endoplasmic reticulum-associated degradation. Herein, we aimed to identify inhibitors to block SND1-MHC-I binding, to facilitate the MHC-I presentation and tumor immunotherapy. Our findings validated the importance of the K490-containing sites in SND1-MHC-I complex. Through structure-based virtual screening and docking analysis, (-)-Epigallocatechin (EGC) exhibited the highest docking score to prevent the binding of MHC-I to SND1 by altering the spatial conformation of SND1. Additionally, EGC treatment resulted in increased expression levels of membrane-presented MHC-I in tumor cells. The C57BL/6J murine orthotopic melanoma model validated that EGC increases infiltration and activity of CD8 T cells in both the tumor and spleen. Furthermore, the combination of EGC with programmed death-1 (PD-1) antibody demonstrated a superior antitumor effect. In summary, we identified EGC as a novel inhibitor of SND1-MHC-I interaction, prompting MHC-I presentation to improve CD8 T cell response within the tumor microenvironment. This discovery presents a promising immunotherapeutic candidate for tumors.
葡萄球菌核酸酶和 tudor 结构域包含蛋白 1（SND1）已被鉴定为一种癌蛋白。我们之前的研究表明，SND1 通过劫持 MHC-I 的新生重链，将其引导至内质网相关降解，从而阻碍主要组织相容性复合体 I（MHC-I）的组装。在此，我们旨在鉴定可阻断 SND1-MHC-I 结合的抑制剂，以促进 MHC-I 的呈递和肿瘤免疫治疗。我们的研究结果验证了 SND1-MHC-I 复合物中包含 K490 位点的重要性。通过基于结构的虚拟筛选和对接分析，（-）-表没食子儿茶素没食子酸酯（EGC）通过改变 SND1 的空间构象，表现出与 MHC-I 结合以防止 SND1 结合的最高对接评分。此外，EGC 处理导致肿瘤细胞中膜呈现 MHC-I 的表达水平增加。C57BL/6J 小鼠原位黑色素瘤模型验证了 EGC 增加了肿瘤和脾脏中 CD8 T 细胞的浸润和活性。此外，EGC 与程序性死亡-1（PD-1）抗体联合显示出更好的抗肿瘤效果。总之，我们确定 EGC 是 SND1-MHC-I 相互作用的新型抑制剂，可促进 MHC-I 的呈递，以改善肿瘤微环境中的 CD8 T 细胞反应。这一发现为肿瘤提供了一种有前途的免疫治疗候选物。
