三级淋巴样结构中的ICOSL+B细胞亚群启动抗肿瘤免疫的机制研究

The tertiary lymphoid structure (TLS) plays a critical role in regional immune response of multiple organs. However, dynamic changes of TLS during oncological therapies and its impact on therapeutic effects remain elusive. In the previous studies, we explored the dynamic changes of tumor microenvironment during treatments by analyzing the clinical samples before and after preoperative (neo-adjuvant) therapies., The findings have been published in Cell(3),Cancer Cell(3),Cancer Discover(2) and Nature Immunol as corresponding authors. In our preliminary experiments, we found a previously unknown B cell subpopulation in breast cancer after preoperative chemotherapy, promoting the activation of T cells in TLS via ICOS-L. Here, 4 research groups cooperate to explore the regional immune response induced by the immunogenic cell death. Using the single-cell sequencing to analyze samples of clinical trials , we will explore the dynamic change of tumor-infiltrating immune cell composition in the process of treatments. Furthermore, we will investigate the function of novel immune checkpoints by establishing animal models which recapitulate tumor microenvironment of patients. Moreover, we will elucidate the underlying molecular mechanisms by protein-RNA interaction techniques which we previously established. This project helps us better understand the regional anti-tumor immune response by conventional anti-tumor treatments and supports the overall goal of this integrated program.

三级淋巴样结构 (TLS) 在多个器官的区域免疫反应中起重要作用，但肿瘤药物治疗中TLS的动态变化及对治疗效果的影响仍不清楚。我们前期通过术前治疗临床试验的标本，动态分析肿瘤微环境在药物治疗中的变化，成果以通讯作者在Cell（3篇）、Cancer Cell（3篇）、Cancer Discover（2篇）、Nature Immunol等杂志发表。预实验发现术前化疗后一群新型B细胞亚群在乳腺癌升高，通过ICOS-L促进TLS中的T细胞激活。在此基础上，本课题集合4个课题组优势，通过单细胞测序分析临床试验标本，探索治疗过程中肿瘤浸润免疫细胞组成的变化；通过构建贴近病人真实微环境的动物模型，阐明新的免疫节点功能；通过前期建立蛋白-RNA互作研究技术，阐明潜在分子机制。本课题有助我们了解在药物治疗下局部区域形成的抗肿瘤免疫反应，符合集成项目的总体目标。

本项目主要围绕“通过临床标本动态观察肿瘤微环境的动态变化，寻找可能的治疗靶点”这一研究内容，揭示了免疫微环境中肿瘤细胞、T细胞、B细胞、巨噬细胞、肝星状细胞、成纤维细胞等的变化及其影响疾病进展的机制。代表性成果为：1)揭示肿瘤微环境B细胞功能转化的机制；2)阐明微环境中成纤维细胞致恶性转化潜能的机制研究；3)揭示核酸信号调控抗肿瘤免疫反应的新机理；4)揭示肿瘤成纤维细胞Fcγ受体调控单抗耐药的机制；5)阐明微环境中嗜酸性粒细胞致恶性转化潜能的机制研究。发表SCI文章19篇，其中IF大于10分16篇，包括Cell本刊2篇，Nature本刊1篇, Nature Immunology, Nature Cell Biology, Cancer Cell, Nature Cancer(2篇), Advanced Science(2篇), Cancer Immunology Research, Journal for Immunotherapy of Cancer(2篇), Clinical Cancer Research , Science Advances, Oncogene, GUT, eLife, RNA Biology等。