Premium
The CD151‐midkine pathway regulates the immune microenvironment in inflammatory breast cancer
Author(s) -
Hayward Steven,
Gachehiladze Mariam,
Badr Nahla,
Andrijes Regina,
Molostvov Guerman,
Paniushkina Liliia,
Sopikova Barbora,
Slobodová Zuzana,
Mgebrishvili Giorgi,
Sharma Nisha,
Horimoto Yoshiya,
Burg Dominic,
Robertson Graham,
Hanby Andrew,
Hoar Fiona,
Rea Daniel,
Eckhardt Bedrich L,
Ueno Naoto T,
Nazarenko Irina,
Long Heather M,
Laere Steven,
Shaaban Abeer M,
Berditchevski Fedor
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5415
Subject(s) - midkine , tetraspanin , immune system , biology , cancer research , chemokine , cancer cell , tumor microenvironment , microbiology and biotechnology , immunology , growth factor , cancer , cell , receptor , biochemistry , genetics
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.