SIRT7去琥珀酰化SHMT2在T细胞氨基酸代谢及抗肿瘤免疫中的作用

PD-1 is a receptor on T cells that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L1) and is suggested to play a role in the maintenance of self-tolerance. PD-L1 expressing on tumor cells confers a potent escaping mechanism from the host T cell immunity and raise the possibility that blockade of PD-1–PD-L1 interaction may provide an effective approach for tumor immunotherapy. Immune checkpoint therapy, especially anti PD-1, anti-PD-L1 and anti CTLA-4 antibody, has provided a very usful weapon against cancer. The goal of the therapy is not to activate the immune system to attack particular targets on tumor cells, but rather to remove inhibitory pathways that block effective antitumor T cell responses. .Given the limitation of current immune checkpoint therapy, the dynamic nature of immune responses to tumors, the complexity of regulation of expression of multiple immune checkpoints and their ligands, it may be difficult to rely on any single immunologic biomarker to treat tumors. It is urgent to identify new target and develop combination therapy to provide curative treatments for many patients..Serine metabolism is required for optimal T cell proliferation by fueling one-carbon metabolism and nucleotide biosynthesis. Furthermore, T cell metabolism has a central role in supporting and shaping immune responses and may have a key role in antitumor immunity. It is reasonable to uncover new targets for cancer immunotherapy and treatment from this pathway..Sirtuins are highly conserved NAD+-dependent protein deacylases. Recent studies have shed light on the critical roles of the seven mammalian sirtuins, SIRT1 to SIRT7, in energy metabolism. We found a link between SIRT7 and T cell serine metabolism.We are going to design four contents in this project. On the basis of generating mice with T-cell-specific depletion of Sirt7, we will study the mechanism of SHMT2 desuccinylated by SIRT7 and the consequence of this interaction in serine metabolic processes and the antitumour activity of T cells. By combination of small molecular of SIRT7 and immune checkpoint therapy , we hope to develop combination therapy to treat tumors. Our research will highlight SIRT7 as a candidate target for regulating T cell serine catabolism as a strategy to block tumor growth.

以抗PD-1和PD-L1抗体为代表的免疫检查点阻断疗法解除了肿瘤细胞对T细胞的免疫抑制，释放T细胞的抗肿瘤活性，堪称人类肿瘤免疫治疗史上的里程碑。但由于这些方法仍存在诸多缺陷，亟需研发新的靶点和联合治疗方案以增强其疗效。丝氨酸代谢对T细胞功能极其重要，从中筛选新靶点，重编程T细胞代谢，用于肿瘤免疫治疗，在理论上可行。我们发现与代谢密切相关的Sirtuins家族成员SIRT7在调控T细胞丝氨酸代谢中有潜在的重要功能。本项目拟在构建T细胞条件敲除Sirt7基因小鼠模型基础上，解析SIRT7通过去琥珀酰化调控丝氨酸代谢途径关键酶SHMT2，影响其酶活性的分子机制，阐明SIRT7调控丝氨酸代谢在抗肿瘤免疫反应中的功能，探讨联合SIRT7小分子调节剂和免疫检查点阻断剂在肿瘤治疗中的效果。本项目从调控免疫细胞氨基酸代谢角度，为肿瘤免疫治疗提供新的视角，无论在基础研究还是潜在的临床应用上都有重要意义。

我们在构建T细胞条件敲除Sirt7基因小鼠模型基础上，发现Sirt7调控了T细胞的激活和细胞因子的分泌，不影响T细胞分化和发育，并通过蛋白质组学、代谢组学等手段解析SIRT7通过去琥珀酰化调控氨基酸代谢途径的多个酶如SHMT2、BCAT2等，影响其酶活性的分子机制，阐明了SIRT7调控氨基酸代谢在抗肿瘤免疫反应中的功能，探讨联合SIRT7小分子调节剂和免疫检查点阻断剂在结肠肿瘤治疗中的效果。项目从调控免疫细胞氨基酸代谢角度，为肿瘤免疫治疗提供新的视角，关于SIRT7调控氨基酸代谢影响结肠癌的论文已经成稿，投递到Nature communication杂志。另外，我们发现SIRT7同家族的另一个成员SIRT5通过调控糖酵解和三羧酸循环中多个代谢酶的蛋白质翻译后修饰，调控了肿瘤代谢和免疫代谢。发现SIRT5通过调控巨噬细胞与胰岛细胞的相互作用，通过调节葡萄糖稳态，调节小鼠的抗感染能力，研究结果发表在2020年的Protein & Cell 杂志。其后，我们构建结肠癌模型，发现SIRT5通过调控氨基酸代谢抑制T细胞活化以及IFN-γ产生，并影响了T细胞分化，从T细胞免疫与肿瘤微环境的角度，为SIRT5 对结肠癌的促进效应提出了新的解释，研究结果发表在2020 年的Journal of Immunology Research杂志。在本项目资助下，共发表5篇研究论文，并受邀撰写Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery部分章节（2021年，Elsevier Academic Press, ISBN: 9780128224670）。还研究了SIRT5调节胆汁酸代谢对肿瘤微环境中巨噬细胞的作用及在肝癌发生发展中的功能，从巨噬细胞免疫与肿瘤微环境的角度，为SIRT5对肿瘤的发生发展提出了新的解释，参与的研究成果发表在2022年的Journal of Hepatology上。