Christopher S McGinnis, Zhuang Miao, Daphne Superville, Winnie Yao, Andrei Goga, Nathan E Reticker-Flynn, Juliane Winkler, Ansuman T Satpathy
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引用次数: 0
摘要
肿瘤转移需要对远处器官微环境进行系统重塑,从而影响免疫细胞表型、群体结构和细胞间通讯。然而,我们对转移龛中免疫表型动态的了解仍不全面。在这里,我们以单细胞分辨率纵向检测了多瘤病毒中间T抗原(PyMT)和4T1转移性乳腺癌模型中的肺部免疫转录谱,从原发性肿瘤发生、转移前生态位形成到转移生长的最后阶段。对这些数据的计算分析表明,外周衍生的和组织驻留的髓样细胞制定了TLR-NFκB炎症程序,该程序与转移前的龛形成相关,并反映了原发肿瘤中CD14+"活化 "的髓样细胞。此外,我们还观察到,在小鼠和人类患者样本中,原发肿瘤和转移龛中的自然杀伤(NK)细胞受到不同程度的调控,转移龛中的细胞毒性 NK 细胞比例升高。最后,我们发现了转移进展过程中细胞类型特异性的 IGF1 和 CCL6 信号动态调控,这代表了抗转移免疫疗法的候选途径。
The temporal progression of lung immune remodeling during breast cancer metastasis.
Tumor metastasis requires systemic remodeling of distant organ microenvironments that impacts immune cell phenotypes, population structure, and intercellular communication. However, our understanding of immune phenotypic dynamics in the metastatic niche remains incomplete. Here, we longitudinally assayed lung immune transcriptional profiles in the polyomavirus middle T antigen (PyMT) and 4T1 metastatic breast cancer models from primary tumorigenesis, through pre-metastatic niche formation, to the final stages of metastatic outgrowth at single-cell resolution. Computational analyses of these data revealed a TLR-NFκB inflammatory program enacted by both peripherally derived and tissue-resident myeloid cells that correlated with pre-metastatic niche formation and mirrored CD14+ "activated" myeloid cells in the primary tumor. Moreover, we observed that primary tumor and metastatic niche natural killer (NK) cells are differentially regulated in mice and human patient samples, with the metastatic niche featuring elevated cytotoxic NK cell proportions. Finally, we identified cell-type-specific dynamic regulation of IGF1 and CCL6 signaling during metastatic progression that represents anti-metastatic immunotherapy candidate pathways.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.