Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
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Published:2023-07-20
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Haake MarkusORCID, Haack Beatrice, Schäfer Tina, Harter Patrick N., Mattavelli Greta, Eiring Patrick, Vashist Neha, Wedekink Florian, Genssler Sabrina, Fischer Birgitt, Dahlhoff Julia, Mokhtari Fatemeh, Kuzkina Anastasia, Welters Marij J. P.ORCID, Benz Tamara M., Sorger LenaORCID, Thiemann Vincent, Almanzar Giovanni, Selle Martina, Thein Klara, Späth JacobORCID, Gonzalez Maria Cecilia, Reitinger CarmenORCID, Ipsen-Escobedo Andrea, Wistuba-Hamprecht KilianORCID, Eichler Kristin, Filipski Katharina, Zeiner Pia S., Beschorner RudiORCID, Goedemans Renske, Gogolla Falk Hagen, Hackl HubertORCID, Rooswinkel Rogier W., Thiem AlexanderORCID, Roche Paula Romer, Joshi HemantORCID, Pühringer Dirk, Wöckel Achim, Diessner Joachim E., Rüdiger ManfredORCID, Leo Eugen, Cheng Phil F.ORCID, Levesque Mitchell P.ORCID, Goebeler MatthiasORCID, Sauer MarkusORCID, Nimmerjahn FalkORCID, Schuberth-Wagner Christine, von Felten StefanieORCID, Mittelbronn MichelORCID, Mehling Matthias, Beilhack AndreasORCID, van der Burg Sjoerd H., Riedel Angela, Weide Benjamin, Dummer ReinhardORCID, Wischhusen JörgORCID
Abstract
AbstractImmune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
Funder
Bayerische Forschungsstiftung Bundesministerium für Bildung und Forschung Deutsche Krebshilfe EC | European Regional Development Fund Deutsche Forschungsgemeinschaft Fonds National de la Recherche Luxembourg
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference70 articles.
1. Osipov, A. et al. Tumor mutational burden, toxicity, and response of immune checkpoint inhibitors targeting PD(L)1, CTLA-4, and combination: a meta-regression analysis. Clin. Cancer Res. 26, 4842–4851 (2020). 2. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014). 3. Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl. Acad. Sci. USA 113, E7759–E7768 (2016). 4. Jerby-Arnon, L. et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997.e924 (2018). 5. Jiang, P. et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med. 24, 1550–1558 (2018).
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