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Cancer Res. 2017 Mar 1;77(5):1083-1096. doi: 10.1158/0008-5472.CAN-16-0598. Epub 2017 Jan 12.

RORγt+ Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers.

Author information

1
Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
2
Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
3
Institute for Mathematical and Molecular Biomedicine, King's College London, London, United Kingdom.
4
Leukocyte Dynamics Group, Beatson Advanced Imaging Resource, CRUK Beatson Institute, Glasgow, United Kingdom.
5
Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, United Kingdom.
6
King's Health Partners Cancer Biobank, King's College London, London, United Kingdom.
7
International Center for Infectiology Research, University of Lyon, Lyon, France.
8
Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
9
Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, United Kingdom.
10
Department of Asthma, Allergy, and Lung Biology, King's College London, London, United Kingdom.
11
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
12
MRC Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
13
UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom.
14
Department of Medical Oncology, Guy's and St Thomas Foundation Trust, London, United Kingdom.
15
ICR, BCN Research Unit, Toby Robins Research Centre, London, United Kingdom.
16
Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom. tony.ng@kcl.ac.uk.

Abstract

Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt+ group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγt+ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. Cancer Res; 77(5); 1083-96. ©2017 AACR.

PMID:
28082403
DOI:
10.1158/0008-5472.CAN-16-0598
[Indexed for MEDLINE]
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