Abstract
Original language | English |
---|---|
Article number | 110447 |
Journal | Cell reports |
Volume | 38 |
Issue number | 9 |
DOIs | |
Publication status | Published - 1 Mar 2022 |
Keywords
- NK cells
- T
- breast cancer
- immunosuppression
- lymph nodes
- metastasis
- organotropism
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In: Cell reports, Vol. 38, No. 9, 110447, 01.03.2022.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche
AU - Kos, Kevin
AU - Aslam, Muhammad A.
AU - van de Ven, Rieneke
AU - Wellenstein, Max D.
AU - Pieters, Wietske
AU - van Weverwijk, Antoinette
AU - Duits, Danique E. M.
AU - van Pul, Kim
AU - Hau, Cheei-Sing
AU - Vrijland, Kim
AU - Kaldenbach, Daphne
AU - Raeven, Elisabeth A. M.
AU - Quezada, Sergio A.
AU - Beyaert, Rudi
AU - Jacobs, Heinz
AU - de Gruijl, Tanja D.
AU - de Visser, Karin E.
N1 - Funding Information: We acknowledge Alexander Rudensky for providing the IRES-DTR-GFP construct, Dr. Emiel J. Th. Rutgers and Dr. Petrousjka van den Tol for provision of clinical samples, and members of the Tumor Biology & Immunology Department, NKI, for their insightful input. We thank the flow cytometry facility, genomics core facility, animal laboratory facility, transgenesis facility, and animal pathology facility of the Netherlands Cancer Institute for technical assistance. This research was funded by NWO Oncology Graduate School Amsterdam (OOA) Diamond Program (K.K.); Netherlands Organisation for Scientific Research grant NWO-VICI 91819616 (K.E.d.V.); Dutch Cancer Society grant KWF10083 , KWF10623 , and KWF13191 (K.E.d.V.), KWF VU2015-7864 (R.v.d.V., T.D.d.G., K.E.d.V.); Oncode Institute (K.E.d.V.); and A Sister's Hope (T.D.d.G.). Components of the graphical abstract were prepared using Servier Medical Art, licensed under Creative Commons Attribution 3.0 Unported License. Funding Information: We acknowledge Alexander Rudensky for providing the IRES-DTR-GFP construct, Dr. Emiel J. Th. Rutgers and Dr. Petrousjka van den Tol for provision of clinical samples, and members of the Tumor Biology & Immunology Department, NKI, for their insightful input. We thank the flow cytometry facility, genomics core facility, animal laboratory facility, transgenesis facility, and animal pathology facility of the Netherlands Cancer Institute for technical assistance. This research was funded by NWO Oncology Graduate School Amsterdam (OOA) Diamond Program (K.K.); Netherlands Organisation for Scientific Research grant NWO-VICI 91819616 (K.E.d.V.); Dutch Cancer Society grant KWF10083, KWF10623, and KWF13191 (K.E.d.V.), KWF VU2015-7864 (R.v.d.V. T.D.d.G. K.E.d.V.); Oncode Institute (K.E.d.V.); and A Sister's Hope (T.D.d.G.). Components of the graphical abstract were prepared using Servier Medical Art, licensed under Creative Commons Attribution 3.0 Unported License. K.K. and K.E.d.V. conceived the ideas and designed the experiments. K.K. performed experiments and data analysis. M.A.A. performed bioinformatical analyses. M.D.W. W.P. A.v.W. and D.D. generated data. K.K. D.K. K.V. C.-S.H. and L.R. performed animal experiments. S.A.Q. and R.B. provided a-CD25-M2A and IL33Trap, respectively. R.v.d.V. K.v.P. and T.D.d.G. collected samples and generated human data. K.E.d.V. supervised the study. K.E.d.V. and K.K. acquired funding. K.K. and K.E.d.V. wrote the paper and prepared the figures with input from all authors. K.E.d.V. reports research funding from Roche/Genentech and is a consultant for Macomics outside the scope of this work. R.v.d.V. reports research funding from Genmab. T.D.d.G. received research support from Idera Pharmaceuticals; advisory/consultancy fees from LAVA Therapeutics, Parner Therapeutics, and Immunicum; and owns stock from LAVA Therapeutics. Publisher Copyright: © 2022 The Author(s)
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
KW - NK cells
KW - T
KW - breast cancer
KW - immunosuppression
KW - lymph nodes
KW - metastasis
KW - organotropism
UR - http://www.scopus.com/inward/record.url?scp=85125220724&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.celrep.2022.110447
DO - https://doi.org/10.1016/j.celrep.2022.110447
M3 - Article
C2 - 35235800
SN - 2211-1247
VL - 38
JO - Cell reports
JF - Cell reports
IS - 9
M1 - 110447
ER -