新辅助免疫化疗后残留食管鳞癌的单细胞分析揭示树突状细胞中 TFAM 介导的免疫调控
Single-Cell Analysis of Residual Esophageal Squamous Cell Carcinoma After Neoadjuvant Immunochemotherapy Reveals TFAM-Mediated Immunoregulation in Dendritic Cells.
作者
作者单位
- West China Hospital of Sichuan University Chengdu China.
- West China Hospital of Sichuan University Chengdu, Sichuan China.
- Third People's Hospital of Chengdu Chengdu, Sichuan China.
- Sichuan University Chengdu China.
- West China Medical Center of Sichuan University Chengdu, Sichuan China.
- West China Hospital of Sichuan University cheng du China.
摘要
中文
新辅助免疫化疗（nICT）已成为食管鳞癌（ESCC）有前景的新辅助治疗策略。识别影响 nICT 应答的因素有助于进一步提高治疗效果。本研究对 14 例接受 nICT 的 ESCC 患者进行单细胞分析，揭示与不同治疗反应相关的肿瘤微环境（TME）特征。非负矩阵分解（NMF）识别出五个具有不同反应关联的协同细胞程序。其中，主要由免疫抑制性细胞亚群组成的 NMF3 程序在微小或无病理肿瘤退缩（TRS3）组中富集，该组中调节性 T 细胞（Tregs）和树突状细胞（DCs）呈现密切相关性。此外，TRS3 组中 DCs 中线粒体转录因子 A（TFAM）表达升高与 Treg 浸润增加相关。髓系特异性 Tfam 敲除小鼠模型显示，TFAM 缺失可逆转免疫抑制性 TME，抑制肿瘤生长，并增强 ESCC 对抗 PD-1 治疗的反应。机制上，DCs 中 TFAM 缺失激活 STING-TBK1-IRF3 通路，从而促进 DC 成熟以增强抗肿瘤免疫。总体而言，本研究刻画了 nICT 后残留 ESCC 的 TME 特征，并揭示 DCs 中 TFAM 表达升高与 nICT 应答不良之间的关联。这些发现表明 DCs 中 TFAM 缺失在激活抗肿瘤免疫中具有关键作用，提示靶向 TFAM 有望提高免疫治疗疗效并优化治疗策略。
English
Neoadjuvant immunochemotherapy (nICT) has emerged as a promising neoadjuvant strategy for esophageal squamous cell carcinoma (ESCC). Identification of the factors affecting the responsiveness to nICT could help further improve treatment efficacy. Here, we performed single-cell analysis on 14 ESCC patients undergoing nICT and revealed tumor microenvironment (TME) features associated with differential treatment responses. Nonnegative matrix factorization (NMF) identified five coordinated cellular programs with distinct response associations. Specifically, the NMF3 program mainly comprising immunosuppressive cell subsets was enriched in the minimal or no pathological tumor regression (TRS3) group, in which regulatory T cells (Tregs) and dendritic cells (DCs) exhibited close correlation. In addition, elevated expression of mitochondrial transcription factor A (TFAM) in DCs was associated with increased Treg infiltration in the TRS3 group. A myeloid-specific Tfam knockout mouse model showed that TFAM deficiency reversed the immunosuppressive TME, inhibited tumor growth, and enhanced response to anti-PD-1 therapy in ESCC. Mechanistically, TFAM deficiency in DCs activated the STING-TBK1-IRF3 pathway, thereby promoting DC maturation to enhance anti-tumor immunity. Overall, this study characterized the TME in residual ESCC after nICT and revealed an association between elevated TFAM expression in DCs and poor responsiveness to nICT. These findings indicate the critical role of TFAM deficiency in DCs in activating anti-tumor immunity, highlighting the potential of targeting TFAM to improve the efficacy of immunotherapy and optimize therapeutic strategies.
分类与指标
- 研究类型
- 基础研究
- 病种
- 食管癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区