title: RORγt+Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers.
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.
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
authors.forename: Sheeba
authors.initials: S
authors.lastname: Irshad
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.|Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Fabian
authors.initials: F
authors.lastname: Flores-Borja
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.|Institute for Mathematical and Molecular Biomedicine, King's College London, London, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lawler
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Monypenny
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Evans
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Male
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.|Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Gordon
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Gazinska
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
authors.forename: Farzana
authors.initials: F
authors.lastname: Noor
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Felix
authors.initials: F
authors.lastname: Wong
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.|Leukocyte Dynamics Group, Beatson Advanced Imaging Resource, CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Gilbert O
authors.initials: GO
authors.lastname: Fruhwirth
authors.affiliation: Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Barber
authors.affiliation: King's Health Partners Cancer Biobank, King's College London, London, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Woodman
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon, France.
authors.forename: Dominic
authors.initials: D
authors.lastname: Patel
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: King's Health Partners Cancer Biobank, King's College London, London, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Owen
authors.affiliation: Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Stewart G
authors.initials: SG
authors.lastname: Martin
authors.affiliation: King's Health Partners Cancer Biobank, King's College London, London, United Kingdom.|Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Pinder
authors.affiliation: King's Health Partners Cancer Biobank, King's College London, London, United Kingdom.|Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, United Kingdom.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Gillett
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Poland
authors.affiliation: Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Ameer-Beg
authors.affiliation: Department of Asthma, Allergy, and Lung Biology, King's College London, London, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: McCaughan
authors.affiliation: Leukocyte Dynamics Group, Beatson Advanced Imaging Resource, CRUK Beatson Institute, Glasgow, United Kingdom.
authors.forename: Leo M
authors.initials: LM
authors.lastname: Carlin
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon, France.
authors.forename: Uzma
authors.initials: U
authors.lastname: Hasan
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Withers
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Lane
authors.affiliation: Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, United Kingdom.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Quezada
authors.affiliation: Department of Medical Oncology, Guy's and St Thomas Foundation Trust, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom.|ICR, BCN Research Unit, Toby Robins Research Centre, London, United Kingdom.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: Tutt
authors.affiliation: Breast Cancer Now (BCN) Research Unit, King's College London, London, United Kingdom. tony.ng@kcl.ac.uk.|Richard Dimbleby, Randall Division & Division of Cancer Studies, King's College London, London, United Kingdom.|UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom.
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D054421:Chemokine CCL21 / Q000276:immunology; D054382:Chemokine CXCL13 / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008207:Lymphatic Metastasis; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D057093:Orphan Nuclear Receptors / Q000276:immunology*; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000473:pathology
chemical_list: D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D057093:Orphan Nuclear Receptors