Abstract
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.
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，我们对转移生态位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-NF-κB炎症程序，该程序与转移前的生态位形成相关，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，原发肿瘤和转移生态位中的自然杀伤（NK）细胞受到不同程度的调控，转移生态位中的细胞毒性NK细胞比例升高。最后，我们确定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，它们代表了抗转移免疫疗法的候选途径。
