功能性肿瘤反应性CD8 + T细胞在胰腺癌中的作用。

IF 12.8 1区 医学 Q1 ONCOLOGY
Hongwei Sun, Changying Shi, Guoqing Fang, Qiufang Guo, Zhengliang Du, Geer Chen, Yasong Wu, Zhe-Sheng Chen, Jian Hua, Yan Zhang, Zhiwen Shi
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引用次数: 0

摘要

背景:传统的检测胰腺癌肿瘤反应性(TR) CD8 +肿瘤浸润淋巴细胞(TILs)的方法通常集中在新抗原表位上,受限于抗原表位范围狭窄,鉴定过程漫长而复杂,导致对TR CD8 + TILs的生物学特性了解不完全。方法:本研究引入了一种将单细胞测序与深度学习(DL)相结合的新方法,该方法可以在不进行新抗原筛选的情况下识别肿瘤反应性CD8 + T细胞。T细胞受体工程T (TCR-T)细胞肿瘤类器官杀伤模型用于验证dl鉴定的TR CD8 + T细胞的功能,而空间转录组学用于确认涉及TR CD8 + TILs的受体-配体相互作用。结果:TR CD8 + TILs的综合分析显示,转录因子FOS调节的线粒体呼吸链相关通路受损。TIGIT-NECTIN2轴被认为是胰腺癌肿瘤微环境中一个重要的免疫检查点分子。T细胞受体(TCR)库分析表明,一些TR CD8 + TILs具有多个TCR αβ组合。此外,使用肿瘤类器官的TCR- t靶向实验显示,与单一类型的TCR相比,多种不同的TR TCR组合具有显著优于TCR的肿瘤杀伤能力。临床上,更高比例的TR CD8 + TILs与胰腺癌患者对新辅助免疫治疗的反应改善和更长的总生存期呈正相关。结论:本研究在对TR TIL生物学的认识上取得了重大进展,为鉴定TR CD8 TIL提供了一种快速、准确的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Functional tumor-reactive CD8 + T cells in pancreatic cancer.

Background: Traditional methods for detecting tumor-reactive (TR) CD8 + tumor-infiltrating lymphocytes (TILs) in pancreatic cancer usually focus on neo-antigenic epitopes, which is limited by the narrow range of antigenic epitopes, and the lengthy and complex identification processes, resulting in an incomplete understanding of the biological characteristics of TR CD8 + TILs.

Methods: This study introduces a novel approach that integrates single-cell sequencing with deep learning (DL), which enables the identification of tumor-reactive CD8 + T cells without neoantigen screening. The T Cell Receptor Engineered T (TCR-T) cell tumor organoid killing model was employed to validate the functionality of DL-identified TR CD8 + T cells, while spatial transcriptomics was used to confirm receptor-ligand interactions involving TR CD8 + TILs.

Results: Comprehensive analyses of TR CD8 + TILs revealed impaired mitochondrial respiratory chain-related pathways regulated by the transcription factor FOS. The TIGIT-NECTIN2 axis was identified as an important immune checkpoint molecule in the tumor microenvironment of pancreatic cancer. T cell receptor (TCR) repertoire analysis demonstrated that some TR CD8 + TILs possess multiple TCR αβ combinations. Furthermore, TCR-T targeting experiments using tumor organoids revealed that combinations of multiple distinct TR TCRs exhibit significantly superior tumor-killing capabilities compared to a single type TCR. Clinically, a higher proportion of TR CD8 + TILs was positively associated with improved responses to neoadjuvant immunotherapy and longer overall survival in pancreatic cancer patients.

Conclusion: This study represents a significant advancement in the understanding of TR TIL biology and provides a rapid and accurate method to identify TR CD8 TILs.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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