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

Kos, K; Aslam, MA; van de Ven, R; Wellenstein, MD; Pieters, W; van Weverwijk, A; Duits, DEM; ... de Visser, KE; + view all (2022) Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche. Cell Reports , 38 (9) , Article 110447. 10.1016/j.celrep.2022.110447. Green open access

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Abstract

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 (Tregs) 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 Tregs during primary tumor growth. Tumor-educated Tregs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as Treg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that Tregs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased Treg/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.

Type: Article
Title: Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2022.110447
Publisher version: https://doi.org/10.1016/j.celrep.2022.110447
Language: English
Additional information: © 2022 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: NK cells, T(regs), breast cancer, immunosuppression, lymph nodes, metastasis, organotropism
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10145129
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