1-磷酸鞘氨醇（S1P）促进结直肠癌微环境中MDSC浸润的机制研究

Colorectal cancer is one of the most common fatal malignancies worldwide. Existing evidence have shown that tumor immuno-microenvironment plays a critical role in the development of cancer. Accumulation of Myeloid-derived suppressor cells (MDSC) in the periphery and local compartments has been proposed to be very critical for shaping tumor immuno-microenvironment. However, the underlying mechanisms remain unlcear. Based on the previous studies, we give the hypothesis: in the milieu of colorectal cancer, sphingosine-1-phosphate (S1P) regulates the proliferation of MDSC via binding its receptors, and drives their infiltration in the periphery and lesions, thereby suppresses anti-tumor immune response, and facilitates tumor growth. In this study, integrating the experiments in vitro and in vivo, we will elucidate signaling pathways responsible for S1P-regulating MDSC accumulation, clarify the identity of cellular sources which predominantly produce S1P, investigate the machanisms underlying MDSC-mediated suppression of anti-tumor immunity, and ultimately demonstrate our hypothesis in multi-layers. In concluision, our work not only provide new insights into the formation of cancer-related immuno-suppressive microenvironment, but also contribute to discover potential therapeutic targets.

结直肠癌是严重威胁人类生命健康的最常见的恶性肿瘤之一。现有的证据表明，肿瘤免疫微环境对肿瘤的发生发展起着重要的作用。髓源性抑制细胞（MDSC）在局部和全身的累积被认为是形成肿瘤免疫微环境的关键步骤。然而，关于肿瘤（特别是结直肠癌）微环境中MDSC产生和累积的调控机制这一重要的科学问题目前仍不甚清楚，亟待解答。本课题组在前期研究的基础上，提出以下科学假设：结直肠癌免疫微环境中，1-磷酸鞘氨醇（S1P）通过与其受体结合，调控MDSC的增殖能力，促进其在外周和病灶中的浸润，从而抑制机体的抗肿瘤免疫应答，利于瘤细胞的生长。本项目拟通过体内外实验，阐明S1P信号调控MDSC的分子机理，明确产生S1P的主要细胞群，探究MDSC抑制抗肿瘤免疫的作用机制，多个层面论证我们的设想。本课题的研究不仅将在肿瘤免疫抑制性微环境的形成机制研究领域产生新的认识，而且将有助于发现潜在的干预靶点。

结直肠癌是严重威胁人类生命健康的最常见的恶性肿瘤之一。现有的证据表明，肿瘤免疫微环境对肿瘤的发生发展起着重要的作用。髓源性抑制细胞（MDSC）在局部和全身中的累积被认为是形成肿瘤免疫微环境的关键步骤。本项目在前期研究的基础上，首先完善和优化了CAC模型制备方案，并检测了模型小鼠MDSC的数量、表型和功能，发现UC癌变过程中主要影响G-MDSC。MDSC的基因芯片和生物信息学分析显示，S1P/S1PR信号对MDSC的产生和功能可能有重要影响。随后，我们用FTY720进行评价，发现FTY720能够促进CAC和CT26移植瘤的生长。机制研究显示，FTY720能够促进MDSC在外周和肿瘤部位的累积，增强MDSC的免疫抑制功能，并且刺激MDSC分泌GM-CSF，并明确了Rho激酶-MAPK/ERK/ELK-1信号通路介导了FTY720的上述效应。本项目的研究不仅加深了人们对肿瘤免疫抑制性微环境的形成机制的认识和了解，而且将为寻找潜在的干预靶点治疗结直肠癌奠定基础。