The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. It is notable that elevated expression of CD151 and a higher number of tumour-infiltrating macrophages correlated with better patient responses to chemotherapy. Accordingly, CD151-expressing IBC xenografts were characterised by the increased infiltration of macrophages. In vitro migration experiments demonstrated that CD151 stimulates the chemoattractive potential of IBC cells for monocytes via mechanisms involving midkine (a heparin-binding growth factor), integrin α6β1, and production of extracellular vesicles (EVs). Profiling of chemokines secreted by IBC cells demonstrated that CD151 increases production of midkine. Purified midkine specifically stimulated migration of monocytes, but not other immune cells. Further experiments demonstrated that the chemoattractive potential of IBC-derived EVs is blocked by anti-midkine antibodies. These results demonstrate for the first time that changes in the expression of a tetraspanin protein by tumour cells can affect the formation of the immune microenvironment by modulating recruitment of effector cells to cancerous tissues. Therefore, a CD151-midkine pathway can be considered as a novel target for controlled changes of the immune landscape in IBC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Breast Unit St James Hospital Leeds Teaching Hospitals NHS Trust Leeds UK

Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Breast Surgical Oncology Juntendo University School of Medicine Tokyo Japan

Department of Clinical and Molecular Pathology Palacký Univerzity Olomouc Czech Republic

Department of Pathology Menoufia University School of Medicine Menoufia Egypt

Faculty of Medicine Institute for Infection Prevention and Hospital Epidemiology Medical Center University of Freiburg Freiburg Germany

German Cancer Consortium Heidelberg Germany

Hospital Sandwell and West Birmingham Hospitals Department of General and Breast Surgery Birmingham UK

Institute of Cancer and Genomic Sciences The University of Birmingham Birmingham UK

Lyramid Sydney Australia

Morgan Welch Inflammatory Breast Cancer Research Program and Clinic Houston TX USA

Olivia Newton John Cancer Research Institute Heidelberg Australia

Translational Cancer Research Unit Center for Oncological Research University Antwerp Antwerp Belgium

University of Leeds Leeds Institute of Cancer and Pathology Leeds Leeds UK

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