Interferon-induced senescent CD8+ T cells reduce anti-PD1 immunotherapy efficacy in early triple-negative breast cancer

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Tong Fu, Xi Jin, Min He, Yi-Yu Chen, Yun-Song Yang, Li Chen, Hu-Yun-Long Zhang, Lei Fan, Jiong Wu, Zhong-Hua Wang, Yi-Wei Chu, Rong-Hua Liu, Yi-Zhou Jiang, Zhi-Ming Shao
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引用次数: 0

Abstract

Triple-negative breast cancers (TNBCs) lack predictive biomarkers to guide immunotherapy, especially during early-stage disease. To address this issue, we used single-cell RNA sequencing, bulk transcriptomics, and pathology assays on samples from 171 patients with early-stage TNBC receiving chemotherapy with or without immunotherapy. Our investigation identified an enriched subset of interferon (IFN)–induced CD8+ T cells in early TNBC samples, which predict immunotherapy nonresponsiveness. Mechanistically, IFN produced by HLA-DR+ monocytes triggered cellular senescence in CD8+ T cells, which was marked by excessive NAD+ consumption, reduced cytotoxicity, and immunotherapy nonresponsiveness. Nicotinamide mononucleotide treatment restored the function of IFN-induced senescent CD8+ T cells and enhanced immunotherapy efficacy in patient-derived organoid–T cell coculture and in mouse models. Overall, our study identifies IFN-induced T cell senescence as a driver of immunotherapy nonresponsiveness in early TNBC and provides a strategy to restore CD8+ T cell function for immunotherapeutic benefit.
干扰素诱导的衰老CD8+ T细胞降低抗pd1免疫治疗早期三阴性乳腺癌的疗效
三阴性乳腺癌(tnbc)缺乏预测性生物标志物来指导免疫治疗,特别是在疾病早期。为了解决这个问题,我们对171例接受化疗或不接受免疫治疗的早期TNBC患者的样本进行了单细胞RNA测序、大量转录组学和病理分析。我们的研究在早期TNBC样本中发现了干扰素(IFN)诱导的CD8+ T细胞的富集亚群,这预示着免疫治疗的无反应性。从机制上讲,HLA-DR+单核细胞产生的IFN触发CD8+ T细胞衰老,其特征是NAD+消耗过多,细胞毒性降低,免疫治疗无反应性。烟酰胺单核苷酸治疗恢复了ifn诱导的衰老CD8+ T细胞的功能,并增强了患者源性类器官- T细胞共培养和小鼠模型的免疫治疗效果。总的来说,我们的研究确定了ifn诱导的T细胞衰老是早期TNBC免疫治疗无反应性的驱动因素,并提供了恢复CD8+ T细胞功能以获得免疫治疗益处的策略。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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