内质网压力信号调控肿瘤相关脾脏造血祖细胞的机制和意义

Myeloid cells are important components of tumor tissues. However, these cells are generally short-lived and must be continuously replenished throughout the progression of cancer. To guarantee a sufficient pool of myeloid cells, cancer interferes with hematopoietic progenitor cell (HPC) activity in bone marrow (BM) and extramedullary organs to induce a systemic deviation of host’s hematopoiesis. To date yet, the functional specialty, mechanism, and clinical relevance of extramedullary hematopoiesis (EMH) remain unclear. We have recently shown that splenic EMH is not a mere quantitative supplement to BM hematopoiesis; in contrast, it exerts unique and significant function by selectively amplifying a specific myeloid-biased HPC subset to generate immunosuppressive myeloid cells and to fuel the tumor-promoting myeloid response. With a distinct capability to produce and response to GM-CSF, these splenic HPCs are committed to generating potent myeloid-derived suppressor cells to repress tumor immunity. Recent advance in our study revealed that this alteration of splenic HPC function was in close association with a significant cellular endoplasmic reticulum (ER) stress response. Based on these findings, we intend to combine experimental studies and clinical sample analysis, to 1) further investigate the regulatory mechanism of tumor-associated splenic myelopoiesis; 2) identify the role of ER stress response in regulating tumor-associated splenic HPC function; and 3) explore the therapeutic potential of targeting these regulatory mechanisms and critical signals. Results obtained from this project would not only provide deeper understanding of the regulatory mechanisms of splenic myelopoiesis in cancer, but may also lead to the development of a novel anti-cancer strategy, which facilitates tumor-eliminating immune activities by restricting immunosuppressive myeloid response at its source.

髓系细胞是肿瘤组织的重要组分，但它们的寿命有限，需要被不断补充以满足肿瘤发展过程中持续增长的需求。因此，肿瘤可显著改变骨髓以及诱导脾脏等髓外器官的造血活动，但其作用及机制尚不清楚。我们前期发现：一类独特的造血祖细胞介导了肿瘤相关的脾脏髓系细胞生成，其功能异于骨髓造血细胞。荷瘤宿主脾脏的造血祖细胞呈现显著的髓系分化偏向，并定向产生免疫抑制功能更强的髓系细胞（JCI，2018）。我们的新近数据提示：内质网压力反应很可能与脾脏造血祖细胞的独特功能密切相关。以此为基础，本项目拟通过实验模型研究和临床样本检测，进一步探索肿瘤相关脾脏髓系细胞生成的机制；明确内质网压力反应及其下游信号在脾脏造血祖细胞发生功能改变过程中的作用，鉴定出关键调控通路；并探讨相关机制对机体抗肿瘤免疫应答及免疫治疗的影响。所得结果不仅有助于我们更好地理解肿瘤诱导脾脏髓系细胞生成的机制，更可为开发新型肿瘤免疫治疗策略提供理论基础。

髓系细胞是肿瘤组织的重要组分，但它们的寿命有限，需要被不断补充以满足肿瘤发展过程中持续增长的需求。我们前期发现：一类独特的造血祖细胞介导了肿瘤相关的脾脏髓系细胞生成，其功能异于骨髓造血细胞，但其作用及机制尚不清楚。在本项目的支持下，我们围绕脾脏髓系细胞生成活动对肿瘤微环境髓系免疫平衡的影响及其调控机制展开研究：1）揭示内质网应激反应引起的PERK-ATF4-C/EBPβ信号轴介导促肿瘤脾脏髓系细胞生成，提示选择性靶向脾脏造血活动是调控髓系免疫平衡、高效低毒的肿瘤免疫治疗新策略；2）解析不同来源、不同功能的髓系细胞对肿瘤微环境的差异性影响，并构建出一个髓系免疫评分（MRS），来反映髓系免疫平衡对机体抗肿瘤免疫应答及治疗的影响。研究成果已在Journal of Experimental Medicine（2022，共同第一作者排第二、共同通讯）、Journal of Clinical Investigation（2020，共同第一作者排第一）、Frontiers in Immunology（2021，独立通讯；2020，特邀综述，单独第一作者）、Frontiers in Molecular Bioscience（2021，最后共同通讯）发表学术论文5篇，申请国家发明专利2项（目前获批1项）。所得结果不仅有助于我们更好地理解肿瘤诱导脾脏髓系细胞生成的机制，更可为选择性阻断促肿瘤髓系细胞来源，实现“从源头纠偏”的肿瘤干预新策略提供理论基础。