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Open Access 01-12-2023 | Research

Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo

Authors: 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 L. 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

Published in: Journal of Hematology & Oncology | Issue 1/2023

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-1^Hi 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 ITGB4^Lo tumors for MDSC-directed immunotherapies.

Graphical Abstract

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Title: Tumor cell integrin β4 and tumor stroma E-/P-selectin cooperatively regulate tumor growth in vivo
Authors: 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 L. 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
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2023
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-023-01413-9

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