Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo
Sandra Genduso, Vera Freytag, Daniela Schetler, Lennart Kirchner, Alina Schiecke, Hanna Maar, Daniel Wicklein, Florian Gebauer, Katharina Bröker, Christine Stürken, Karin Milde‐Langosch, Leticia Oliveira‐Ferrer, Franz Ricklefs, Florian Ewald, Gerrit Wolters‐Eisfeld, Kristoffer Riecken, Ludmilla Unrau, Linda Krause, Hanibal Bohnenberger, Anne Offermann, Sven Perner, Susanne Sebens, Katrin Lamszus, Linda Diehl, Stefan Linder, Manfred Jücker, Udo Schumacher, Tobias Lange
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: 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: tumors for MDSC-directed immunotherapies.