Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokhtari F, Kuzkina A, Welters MJ, Benz TM, Sorger L, Thiemann V, Almanzar G, Selle M, Thein K, Späth J, Gonzalez MC, Reitinger C, Ipsen Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rooswinkel RW, Thiem A, Roche PR, Joshi H, Pühringer D, Wöckel A, Diessner JE, Rüdiger M, Leo E, Cheng PF, Levesque MP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, Wischhusen J (2023)

Publication Language: English

Publication Type: Journal article

Publication year: 2023

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 14

Article Number: 4253

Journal Issue: 1

DOI: 10.1038/s41467-023-39817-3

Abstract

Immune 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.

Authors with CRIS profile

Carmen Reitinger Lehrstuhl für Genetik Andrea Ipsen Escobedo Lehrstuhl für Genetik Falk Nimmerjahn Lehrstuhl für Genetik

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE) CatalYm GmbH DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Leiden University Medical Center NL Netherlands (NL) Medizinische Universität Innsbruck AT Austria (AT) Forbion NL Netherlands (NL) Universitätsspital Basel CH Switzerland (CH) Julius-Maximilians-Universität Würzburg DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH) oikostat GmbH CH Switzerland (CH) Luxembourg Institute of Health (CRP-Santé) LU Luxembourg (LU)

How to cite

APA:

Haake, M., Haack, B., Schäfer, T., Harter, P.N., Mattavelli, G., Eiring, P.,... Wischhusen, J. (2023). Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-39817-3

MLA:

Haake, Markus, et al. "Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment." Nature Communications 14.1 (2023).

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