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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| Published in: | Cell reports (Cambridge) Vol. 38; no. 9; p. 110447 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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01.03.2022
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| ISSN: | 2211-1247 |
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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 (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. |
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| AbstractList | 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. |
| Author | Quezada, Sergio A Pieters, Wietske van de Ven, Rieneke van Weverwijk, Antoinette Vrijland, Kim Hau, Cheei-Sing Kaldenbach, Daphne de Gruijl, Tanja D Duits, Danique E M Kos, Kevin de Visser, Karin E Raeven, Elisabeth A M Wellenstein, Max D Aslam, Muhammad A van Pul, Kim Jacobs, Heinz Beyaert, Rudi |
| Author_xml | – sequence: 1 givenname: Kevin surname: Kos fullname: Kos, Kevin organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 2 givenname: Muhammad A surname: Aslam fullname: Aslam, Muhammad A organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan – sequence: 3 givenname: Rieneke surname: van de Ven fullname: van de Ven, Rieneke organization: Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam and Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, the Netherlands – sequence: 4 givenname: Max D surname: Wellenstein fullname: Wellenstein, Max D organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 5 givenname: Wietske surname: Pieters fullname: Pieters, Wietske organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands – sequence: 6 givenname: Antoinette surname: van Weverwijk fullname: van Weverwijk, Antoinette organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 7 givenname: Danique E M surname: Duits fullname: Duits, Danique E M organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 8 givenname: Kim surname: van Pul fullname: van Pul, Kim organization: Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam and Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, the Netherlands – sequence: 9 givenname: Cheei-Sing surname: Hau fullname: Hau, Cheei-Sing organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 10 givenname: Kim surname: Vrijland fullname: Vrijland, Kim organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 11 givenname: Daphne surname: Kaldenbach fullname: Kaldenbach, Daphne organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 12 givenname: Elisabeth A M surname: Raeven fullname: Raeven, Elisabeth A M organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands – sequence: 13 givenname: Sergio A surname: Quezada fullname: Quezada, Sergio A organization: Cancer Immunology Unit, University College London Cancer Institute, WC1E 6DD London, UK – sequence: 14 givenname: Rudi surname: Beyaert fullname: Beyaert, Rudi organization: Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, VIB, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium – sequence: 15 givenname: Heinz surname: Jacobs fullname: Jacobs, Heinz organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands – sequence: 16 givenname: Tanja D surname: de Gruijl fullname: de Gruijl, Tanja D organization: Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam and Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, the Netherlands – sequence: 17 givenname: Karin E surname: de Visser fullname: de Visser, Karin E email: k.d.visser@nki.nl organization: Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: k.d.visser@nki.nl |
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| Keywords | NK cells lymph nodes T(regs) metastasis breast cancer immunosuppression organotropism |
| Language | English |
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| SubjectTerms | Animals Breast Neoplasms - pathology Carcinogenesis - pathology Female Humans Killer Cells, Natural - pathology Lymph Nodes Lymphatic Metastasis - pathology Mice |
| Title | Tumor-educated T regs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche |
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