Author:
Genduso Sandra,Freytag Vera,Schetler Daniela,Kirchner Lennart,Schiecke Alina,Maar Hanna,Wicklein Daniel,Gebauer Florian,Bröker Katharina,Stürken Christine,Milde-Langosch Karin,Oliveira-Ferrer Leticia,Ricklefs Franz L.,Ewald Florian,Wolters-Eisfeld Gerrit,Riecken Kristoffer,Unrau Ludmilla,Krause Linda,Bohnenberger Hanibal,Offermann Anne,Perner Sven,Sebens Susanne,Lamszus Katrin,Diehl Linda,Linder Stefan,Jücker Manfred,Schumacher Udo,Lange Tobias
Abstract
Abstract
Background
The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.
Methods
We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.
Results
We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b+ Gr-1Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes.
Conclusions
These findings suggest a distinct vulnerability of ITGB4Lo tumors for MDSC-directed immunotherapies.
Graphical Abstract
Funder
Deutsche Forschungsgemeinschaft
Universitätsklinikum Hamburg-Eppendorf (UKE)
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Biology,Hematology
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