Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche
Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche
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DOI：
10.1016/j.celrep.2022.110447
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发表时间：
2022-03-01
期刊：
影响因子：
8.8
通讯作者：
de Visser, Karin E.
中科院分区：
文献类型：
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作者：
Kos, Kevin;Aslam, Muhammad A.;de Visser, Karin E.
乳腺癌伴有全身性免疫抑制，这有助于转移的形成，但这如何形成转移的向器官性尚不清楚。在这里，我们研究了乳腺肿瘤发生对远端器官中调节性T细胞（T-T细胞）的影响，以及这如何影响多器官转移性疾病。使用临床前小鼠乳腺肿瘤模型，重现人类转移性乳腺癌，我们观察到系统的积累，激活，高度免疫抑制性T细胞在原发性肿瘤生长。受肿瘤训练的T-T细胞显示了对乳腺肿瘤发生的组织特异性转录重布线。这对转移的器官向性具有功能性后果，因为T-reg耗竭减少了向肿瘤引流淋巴结的转移，但不减少向肺的转移。从机制上讲，我们发现T-reg控制淋巴结中的自然杀伤（NK）细胞活化，从而促进淋巴结转移。与健康对照相比，在乳腺癌患者的前哨淋巴结中观察到增加的T-reg/NK细胞比率。这项研究强调了转移性疾病的免疫调节是高度器官依赖性的。
Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (T-regs) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive T-regs during primary tumor growth. Tumor-educated T-regs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as T-reg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that T-regs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis, In line, an increased T-reg/NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent.