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

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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

Supplementary Information

The online version contains supplementary material available at 10.1186/s13045-023-01413-9.

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Most cited references 55

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Myeloid-derived suppressor cells as regulators of the immune system.

Dmitry I. Gabrilovich, Srinivas Nagaraj (2009)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

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Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

Vincenzo Bronte, Sven Brandau, Shu-hsia Chen … (2016)

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population expanded in cancer and other chronic inflammatory conditions. Here the authors identify the challenges and propose a set of minimal reporting guidelines for mouse and human MDSC.

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Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression

Christopher L. Groth, Xiaoying Hu, Rebekka Weber … (2018)

Under steady-state conditions, bone marrow-derived immature myeloid cells (IMC) differentiate into granulocytes, macrophages and dendritic cells (DCs). This differentiation is impaired under chronic inflammatory conditions, which are typical for tumour progression, leading to the accumulation of IMCs. These cells are capable of inducing strong immunosuppressive effects through the expression of various cytokines and immune regulatory molecules, inhibition of lymphocyte homing, stimulation of other immunosuppressive cells, depletion of metabolites critical for T cell functions, expression of ectoenzymes regulating adenosine metabolism, and the production of reactive species. IMCs are therefore designated as myeloid-derived suppressor cells (MDSCs), and have been shown to accumulate in tumour-bearing mice and cancer patients. MDSCs are considered to be a strong contributor to the immunosuppressive tumour microenvironment and thus an obstacle for many cancer immunotherapies. Consequently, numerous studies are focused on the characterisation of MDSC origin and their relationship to other myeloid cell populations, their immunosuppressive capacity, and possible ways to inhibit MDSC function with different approaches being evaluated in clinical trials. This review analyses the current state of knowledge on the origin and function of MDSCs in cancer, with a special emphasis on the immunosuppressive pathways pursued by MDSCs to inhibit T cell functions, resulting in tumour progression. In addition, we describe therapeutic strategies and clinical benefits of MDSC targeting in cancer.

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Author and article information

Contributors

Tobias Lange: tobias.lange@med.uni-jena.de

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 17 March 2023

Publication date PMC-release: 17 March 2023

Publication date Collection: 2023

Volume: 16

Electronic Location Identifier: 23

Affiliations

[1 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Anatomy and Experimental Morphology, , University Medical Center Hamburg-Eppendorf, ; Martinistrasse 52, 20246 Hamburg, Germany

[2 ]GRID grid.275559.9, ISNI 0000 0000 8517 6224, Institute of Anatomy I, Cancer Center Central Germany, , Jena University Hospital, ; Teichgraben 7, 07743 Jena, Germany

[3 ]GRID grid.10253.35, ISNI 0000 0004 1936 9756, Department of Anatomy and Cell Biology, , University of Marburg, ; Robert-Koch-Strasse 8, 35037 Marburg, Germany

[4 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of General, Visceral and Thoracic Surgery, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[5 ]GRID grid.411097.a, ISNI 0000 0000 8852 305X, Department of General, Visceral and Thoracic Surgery, , University Hospital Cologne, ; Kerpener Strasse 62, 50937 Cologne, Germany

[6 ]GRID grid.461732.5, Faculty of Medicine, , MSH Medical School Hamburg, Medical University, ; 20251 Hamburg, Germany

[7 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Gynecology, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[8 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Neurosurgery, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[9 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Biochemistry and Signal Transduction, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[10 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Pediatric Hematology and Oncology, , Research Institute Childrens’ Cancer Center, University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[11 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[12 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institue of Experimental Immunology and Hepatology, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[13 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Medical Biometry and Epidemiology, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[14 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Institute of Pathology, , University Medical Center Göttingen, ; Robert-Koch-Strasse 40, 37075 Göttingen, Germany

[15 ]GRID grid.4562.5, ISNI 0000 0001 0057 2672, Institute of Pathology, , University of Lübeck and University Medical Center Schleswig-Holstein, ; Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany

[16 ]GRID grid.412468.d, ISNI 0000 0004 0646 2097, Institute for Experimental Cancer Research, , Kiel University (CAU) and University Medical Center Schleswig-Holstein, ; Campus Kiel, Arnold-Heller-Strasse 3, 24105 Kiel, Germany

[17 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Institute of Medical Microbiology, Virology and Hygiene, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany

[18 ]GRID grid.466457.2, ISNI 0000 0004 1794 7698, Medical School Berlin, ; Leipziger Platz 10, 10117 Berlin, Germany

Article

Publisher ID: 1413

DOI: 10.1186/s13045-023-01413-9

PMC ID: 10022201

PubMed ID: 36932441

SO-VID: e6c97719-ad9a-473e-b9c8-4ad12993621d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 8 September 2022

Date accepted : 13 February 2023

Funding

Funded by: Deutsche Forschungsgemeinschaft

Award ID: 246505577

Award Recipient : Sandra Genduso Alina Schiecke Hanna Maar Tobias Lange

Funded by: Universitätsklinikum Hamburg-Eppendorf (UKE) (5411)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: integrin β4,e-selectin,p-selectin,myeloid-derived suppressor cell,anoikis,tumor-infiltrating leukocyte,chemoattraction

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: integrin β4, e-selectin, p-selectin, myeloid-derived suppressor cell, anoikis, tumor-infiltrating leukocyte, chemoattraction

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

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Abstract

Background

Methods

Results

Conclusions

Graphical Abstract

Supplementary Information

Related collections

Cancer Immunotherapy

Most cited references 55

Myeloid-derived suppressor cells as regulators of the immune system.

Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression

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