碳酸锂抗肿瘤新机制探究：调节糖原代谢再教育肿瘤相关巨噬细胞

Cancer Immunotherapy that lies on innate immune responses has not been well established yet. Macrophages play critical roles in innate immune system. Although macrophages are capable of killing tumor cells, typically for so-called M1 macrophages, they are commonly educated into M2 macrophages, which promote tumor angiogenesis, tumor escaping and metastasis. Targeting these M2 macrophages holds great potential in cancer immunotherapy. Previous studies have revealed that there are some obvious differences between M1 and M2 macrophages in metabolic mode. Our investigations also indicated that M1 phenotype is regulated by glycolysis pathway. Increased glycolysis may contribute to the reprogramming of M2 to M1 phenotype. Based on the above findings, we hypothesize that lithium carbonate which is a classical inhibitor of GSK-3βcould reeducate M2 tumor-promoting macrophages into M1 tumor-inhibiting macrophages by restoring Gys1 activity and increasing glycogen synthesis. We aim to investigate the effects of lithium carbonate on macrophage polarization, bioactivity and the underlying mechanisms. We will also investigate how lithium carbonate ameliorates tumor immune microenvironment and suppress tumor growth by reeducating M2 macrophages. This project will reveal the anti-tumor immune responses and mechanisms of lithium carbonate, and pave the way for tumor immunotherapy utilizing innate immune system.

巨噬细胞作为固有免疫应答的核心成分，虽具有强大的抗肿瘤潜质，但受肿瘤教育反而转变为促进肿瘤发展的M2型巨噬细胞。目前M2型肿瘤相关巨噬细胞已成为肿瘤免疫治疗的新靶点，但仍缺乏理想手段。已有研究指出，M1与M2巨噬细胞糖代谢途径存在明显差异。申请人的前期研究结果也表明，巨噬细胞M1表型受糖原代谢的调控，增强巨噬细胞糖原代谢有望将M2巨噬细胞逆转为M1巨噬细胞。基于此，本项目提出假设：通过碳酸锂抑制GSK-3β，恢复糖原合酶Gys1活性，增加糖原合成，进而将肿瘤相关的M2型巨噬细胞再教育成为抗肿瘤的M1型巨噬细胞。本项目拟对不同巨噬细胞亚群，分析碳酸锂对其表型和功能的影响，进而阐明其内在分子机制，同时探究碳酸锂通过对M2型巨噬细胞的再教育，对肿瘤免疫微环境的重塑及其抗肿瘤功效。本项目有望揭示老药碳酸锂抗肿瘤作用的免疫学机理和途径，开发以固有免疫为基础的抗肿瘤免疫新疗法。

巨噬细胞作为固有免疫应答的核心成分，在肿瘤免疫应答、炎症性反应中均具有重要作用。我们发现糖原代谢是控制巨噬细胞介导的炎症反应的重要事件。IFN-γ/LPS治疗刺激巨噬细胞合成糖原，糖原通过糖原分解生成G6P，进一步通过戊糖磷酸途径产生丰富的NADPH，确保高水平的还原性谷胱甘肽，使炎症巨噬细胞存活。同时，糖原代谢也增加了巨噬细胞中UDPG水平和P2Y14受体。UDPG/P2Y14信号通路不仅通过激活RARβ上调STAT1的表达，还通过下调磷酸酶TC45促进STAT1的磷酸化。通过增强这种代谢途径有助于逆转肿瘤微环境中的M2型促肿瘤巨噬细胞向M1型炎性抑肿瘤巨噬细胞的计划。而另一方面，阻断这种糖原代谢途径会破坏多个小鼠模型的急性炎症反应。糖原代谢也调节脓毒症患者的炎症反应。这些发现表明巨噬细胞中的糖原代谢是一种重要的调节因子，并为治疗急性炎症性疾病提供了策略。该研究对于新冠肺炎引起的炎症因子风暴的治疗及肿瘤免疫治疗这两个领域均有重要意义。