Tumor-educated T regs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche

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 ) in distant organs and how this affects multi-o...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 38; H. 9; S. 110447
Hauptverfasser: Kos, Kevin, Aslam, Muhammad A, van de Ven, Rieneke, Wellenstein, Max D, Pieters, Wietske, van Weverwijk, Antoinette, Duits, Danique E M, van Pul, Kim, Hau, Cheei-Sing, Vrijland, Kim, Kaldenbach, Daphne, Raeven, Elisabeth A M, Quezada, Sergio A, Beyaert, Rudi, Jacobs, Heinz, de Gruijl, Tanja D, de Visser, Karin E
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.03.2022
Schlagworte:
Animals
Breast Neoplasms - pathology
Carcinogenesis - pathology
Female
Humans
Killer Cells, Natural - pathology
Lymph Nodes
Lymphatic Metastasis - pathology
Mice
NK cells
lymph nodes
T(regs)
metastasis
breast cancer
immunosuppression
organotropism
ISSN:2211-1247
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Zusammenfassung: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 ) 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 during primary tumor growth. Tumor-educated T show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as T depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that T control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased T /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.
ISSN:2211-1247
DOI:10.1016/j.celrep.2022.110447