Liu Xiaowei, Song Jinen, Yuan Meiling, Zuo Fengli, Li Huihui, Tang Leyi, Wang Xinmin, Wang Xueyan, Xiao Qian, Li Li, Liu Xinyu, Yang Zhankun, Wu Jianlin, Jing Jing, Ma Xuelei, Shi Hubing
Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China.
Signal Transduct Target Ther. 2025 Jun 9;10(1):182. doi: 10.1038/s41392-025-02265-0.
How the host immune system loses its surveillance function during the evolution from normal cell to malignancy is still largely unknown. Here, we investigate the dynamics changes of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment by profiling 132,115 single-cell transcriptomes derived from 51 tissues, including healthy pancreatic tissue, non-metastatic PDAC primary tumors, metastatic primary tumors, and patient-matched liver metastases. The cellular proportion, bio-functional, and interaction between each cell type are carefully characterized. Aberrant copy number variations (CNVs) indicating malignant intensity are identified at chromosomes 7 and 20 of epithelial cells during tumor development. A bio-functional transition of predominant genes from physiology to pancreatic oncogenesis and metastasis is observed. Combinatorial analysis of epithelial cells and immunocytes indicates a gradient loss of immune surveillance during the malignant transformation. By dissecting cellular interaction, we unravel an incremental tumor cell-triggered apoptosis of DCs through molecular pair ANXA1-FPR1/3. Consequently, the activation and infiltration of cytotoxic CD8 T cells are dampened progressively. Remarkably, we unveil a novel subtype of stress-response NK cells (strNK), which are characterized by robust proliferation, diminished cytolytic capabilities, and negative immune regulation. Notably, the presence of strNK cells is associated with poor prognosis of PDAC patients, implying a potential pro-tumor function. Taken together, our results not only shed light on the intricate mechanisms underlying step-wise evasion of immune surveillance during PDAC tumor development, but also provide a potential strategy for holding back malignant transition by reinforcing DCs' function.
在从正常细胞演变为恶性肿瘤的过程中，宿主免疫系统如何丧失其监视功能在很大程度上仍然未知。在这里，我们通过分析来自51个组织的132,115个单细胞转录组来研究胰腺导管腺癌（PDAC）肿瘤微环境的动态变化，这些组织包括健康胰腺组织、非转移性PDAC原发性肿瘤、转移性原发性肿瘤以及患者匹配的肝转移灶。我们仔细表征了每种细胞类型的细胞比例、生物功能以及它们之间的相互作用。在肿瘤发展过程中，在上皮细胞的7号和20号染色体上发现了指示恶性强度的异常拷贝数变异（CNV）。观察到主要基因从生理功能到胰腺肿瘤发生和转移的生物功能转变。上皮细胞和免疫细胞的组合分析表明，在恶性转化过程中免疫监视功能呈梯度丧失。通过剖析细胞间相互作用，我们揭示了肿瘤细胞通过分子对ANXA1-FPR1/3触发树突状细胞（DC）的渐进性凋亡。因此，细胞毒性CD8 T细胞的激活和浸润逐渐受到抑制。值得注意的是，我们发现了一种新型的应激反应性自然杀伤细胞（strNK）亚型，其特征是增殖旺盛、细胞溶解能力减弱以及负性免疫调节。值得注意的是，strNK细胞的存在与PDAC患者的不良预后相关，这意味着其具有潜在的促肿瘤功能。综上所述，我们的研究结果不仅揭示了PDAC肿瘤发展过程中逐步逃避免疫监视的复杂机制，还为通过增强DC功能来阻止恶性转化提供了潜在策略。
