肿瘤细胞治疗研究
英文原题：Functional tumor-reactive CD8 + T cells in pancreatic cancer.
本研究代表了对 TR TIL 生物学认识的重要进展，并提供了一种快速准确鉴定 TR CD8 TIL 的方法。
背景：目前检测胰腺癌肿瘤反应性（TR）CD8⁺ TIL 的传统方法通常聚焦新抗原表位，受抗原表位范围狭窄及鉴定过程漫长复杂限制，导致对 TR CD8⁺ TIL 生物学特征的认识不完整。方法：本研究提出一种结合单细胞测序和深度学习（DL）的新方法，无需筛选新抗原即可识别肿瘤反应性 CD8⁺ T 细胞。采用 TCR 工程化 T 细胞（TCR-T）肿瘤类器官杀伤模型验证 DL 鉴定的 TR CD8⁺ T 细胞功能，并通过空间转录组学确认 TR CD8⁺ TIL 相关受体-配体相互作用。结果：对 TR CD8⁺ TIL 的全面分析发现，FOS 转录因子调节的线粒体呼吸链相关通路受损。TIGIT-NECTIN2 轴被确定为胰腺癌 TME 中重要的免疫检查点分子。TCR 库分析显示，部分 TR CD8⁺ TIL 具有多种 TCR 组合。此外，使用肿瘤类器官进行 TCR-T 靶向实验发现，多种不同 TR TCR 组合的肿瘤杀伤能力显著优于单一类型 TCR。临床上，TR CD8⁺ TIL 比例较高与胰腺癌患者新辅助免疫治疗应答改善和总生存期延长正相关。结论：本研究显著推进了对肿瘤反应性 TIL 生物学的理解，并提供一种快速、准确识别 TR CD8⁺ TIL 的方法。
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 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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