Augmenting antitumor efficacy of Th17-derived Th1 cells through IFN-γ-induced type I interferon response network via IRF7

• 成果类型: Article
• 署名作者: Lei, Xiaoyi; Xiao, Ruipei; Chen, Zhe; Ren, Jie; Zhao, Wenli; Tang, Wenting; Wen, Kang; Zhu, Yihan; Li, Xinru; Ouyang, Suidong; Xu, Abai; Hu, Yu; Bi, Enguang
• 署名单位: Southern Medical University - China; Southern Medical University - China; Southern Medical University - China; Guangdong Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9487
• DOI: 10.1073/pnas.2412120121
• 发表日期: 2024-11-19
• 关键词: t-cells; adoptive immunotherapy; persistence; phenotype; features; receptor; PATHWAY; driven; helper; il-21

摘要

The importance of CD4+T cells in cancer immunotherapy has gained increasing recognition. Particularly, a specific subset of CD4+ T cells coexpressing the T helper type 1 (Th1) and Th17 markers has demonstrated remarkable antitumor potential. However, the underlying mechanisms governing the differentiation of these cells and their subsequent antitumor responses remain incompletely understood. Single- cell RNA sequencing (scRNA-seq) data reanalysis demonstrated the presence of Th171 cells within tumors. Subsequent trajectory analysis found that these Th171 cells are initially primed under Th17 conditions and then converted into IFN-gamma-producing cells. Following the in vivo differentiation trajectory of Th171 cells, we successfully established in vitro Th171 cell culture. Transcriptomic profiling has unveiled a substantial resemblance between in vitro- generated Th171 cells and their tumor- infiltrating counterparts. Th171 cells exhibit more potent antitumor responses than Th1 or Th17 cells. Additionally, Th171chimeric antigen receptor T (CAR- T) cells eradicate solid tumors more efficiently. Importantly, Th171 cells display an early exhaustion phenotype while retaining stemness. Mechanistically, Th171 cells migrate faster and accumulate more in tumors in an extracellular matrix protein 1 (ECM1)-dependent manner. Furthermore, we show that IFN-gamma up- regulated IRF7 to promote the type I interferon response network and ECM1 expression but decreased the exhaustion status in Th171 cells. Taken together, our findings position Th171 cells as a great candidate for improving targeted immunotherapies in solid malignancies.