Reprogramming intratumoral Treg cells by morpholino-mediated splicing of FOXP3 for cancer immunotherapy

IF 16.3 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-08-22 DOI:10.1126/sciimmunol.adr9933

Yujing Li, Naresh Singh, Chuanpeng Dong, Samantha Sharma, Zhuolong Zhou, Jianguang Du, Maya Haouili, Yile Jiao, Emily Hopewell, Yunlong Liu, Mateusz Opyrchal, Xinna Zhang, Baohua Zhou, Xiongbin Lu

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引用次数: 0

Abstract

Regulatory T cells (T_reg cells) represent a primary barrier to the development of effective antitumor immunity. Here, we report that reprogramming T_reg cells by shifting the expression of FOXP3 from its full-length isoform (FOXP3^FL) to a short isoform with exon 2 skipped (FOXP3^dE2) promotes CD8 T cell–mediated antitumor immunity. FOXP3^dE2 mRNA expression in triple-negative breast cancer tissue positively correlated with overall patient survival. Mice expressing only the FOXP3^dE2 isoform were resistant to the development of multiple types of tumors. Tumor-infiltrating T_reg cells expressing the FOXP3^dE2 isoform exhibited lower immunosuppressive activity and promoted CD8 T cell activation. In addition, we designed a morpholino oligo to induce FOXP3 exon 2 skipping, which similarly enhanced antitumor activity in mouse tumor models and the killing capacity of autologous tumor-infiltrating T cells against patient-derived tumor organoids. Our results suggest that promoting FOXP3^dE2 expression reprograms T_reg cells to T helper–like cells, thereby enhancing antitumor immunity.

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通过morpholinos介导的FOXP3剪接对肿瘤内Treg细胞进行重编程

调节性T细胞（Treg细胞）是发展有效抗肿瘤免疫的主要屏障。在这里，我们报道通过将FOXP3的表达从其全长异构体（FOXP3FL）转移到外显子2跳过的短异构体（FOXP3dE2）来重编程Treg细胞可促进CD8 T细胞介导的抗肿瘤免疫。FOXP3dE2 mRNA在三阴性乳腺癌组织中的表达与患者总体生存率呈正相关。仅表达FOXP3dE2亚型的小鼠对多种类型肿瘤的发展具有抗性。表达FOXP3dE2亚型的肿瘤浸润性Treg细胞表现出较低的免疫抑制活性，并促进CD8 T细胞的活化。此外，我们设计了一种morpholino oligo来诱导FOXP3外显子2跳变，这同样增强了小鼠肿瘤模型的抗肿瘤活性和自体肿瘤浸润T细胞对患者来源的肿瘤类器官的杀伤能力。我们的研究结果表明，促进FOXP3dE2的表达将Treg细胞重编程为T辅助细胞，从而增强抗肿瘤免疫。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.