Nature Communications (Jul 2023)
Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
- Markus Haake,
- Beatrice Haack,
- Tina Schäfer,
- Patrick N. Harter,
- Greta Mattavelli,
- Patrick Eiring,
- Neha Vashist,
- Florian Wedekink,
- Sabrina Genssler,
- Birgitt Fischer,
- Julia Dahlhoff,
- Fatemeh Mokhtari,
- Anastasia Kuzkina,
- Marij J. P. Welters,
- Tamara M. Benz,
- Lena Sorger,
- Vincent Thiemann,
- Giovanni Almanzar,
- Martina Selle,
- Klara Thein,
- Jacob Späth,
- Maria Cecilia Gonzalez,
- Carmen Reitinger,
- Andrea Ipsen-Escobedo,
- Kilian Wistuba-Hamprecht,
- Kristin Eichler,
- Katharina Filipski,
- Pia S. Zeiner,
- Rudi Beschorner,
- Renske Goedemans,
- Falk Hagen Gogolla,
- Hubert Hackl,
- Rogier W. Rooswinkel,
- Alexander Thiem,
- Paula Romer Roche,
- Hemant Joshi,
- Dirk Pühringer,
- Achim Wöckel,
- Joachim E. Diessner,
- Manfred Rüdiger,
- Eugen Leo,
- Phil F. Cheng,
- Mitchell P. Levesque,
- Matthias Goebeler,
- Markus Sauer,
- Falk Nimmerjahn,
- Christine Schuberth-Wagner,
- Stefanie von Felten,
- Michel Mittelbronn,
- Matthias Mehling,
- Andreas Beilhack,
- Sjoerd H. van der Burg,
- Angela Riedel,
- Benjamin Weide,
- Reinhard Dummer,
- Jörg Wischhusen
Affiliations
- Markus Haake
- Department of Gynecology, University Hospital Würzburg
- Beatrice Haack
- Department of Gynecology, University Hospital Würzburg
- Tina Schäfer
- Department of Gynecology, University Hospital Würzburg
- Patrick N. Harter
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
- Greta Mattavelli
- Mildred Scheel Early Career Center, University Hospital of Würzburg
- Patrick Eiring
- Department of Biotechnology and Biophysics, Julius Maximilians University Würzburg, Am Hubland
- Neha Vashist
- Department of Gynecology, University Hospital Würzburg
- Florian Wedekink
- Department of Gynecology, University Hospital Würzburg
- Sabrina Genssler
- CatalYm GmbH
- Birgitt Fischer
- Department of Gynecology, University Hospital Würzburg
- Julia Dahlhoff
- Department of Medicine II, University Hospital of Würzburg
- Fatemeh Mokhtari
- Department of Medicine II, University Hospital of Würzburg
- Anastasia Kuzkina
- Department of Gynecology, University Hospital Würzburg
- Marij J. P. Welters
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center
- Tamara M. Benz
- Department of Gynecology, University Hospital Würzburg
- Lena Sorger
- Department of Gynecology, University Hospital Würzburg
- Vincent Thiemann
- Department of Gynecology, University Hospital Würzburg
- Giovanni Almanzar
- Department of Gynecology, University Hospital Würzburg
- Martina Selle
- Department of Gynecology, University Hospital Würzburg
- Klara Thein
- Department of Gynecology, University Hospital Würzburg
- Jacob Späth
- Department of Gynecology, University Hospital Würzburg
- Maria Cecilia Gonzalez
- CatalYm GmbH
- Carmen Reitinger
- Division of Genetics, Department of Biology, University of Erlangen
- Andrea Ipsen-Escobedo
- Division of Genetics, Department of Biology, University of Erlangen
- Kilian Wistuba-Hamprecht
- Department of Dermatology, University Medical Center Tübingen
- Kristin Eichler
- Department of Gynecology, University Hospital Würzburg
- Katharina Filipski
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
- Pia S. Zeiner
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
- Rudi Beschorner
- Department of Neuropathology, University of Tübingen
- Renske Goedemans
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center
- Falk Hagen Gogolla
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck
- Hubert Hackl
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck
- Rogier W. Rooswinkel
- Forbion
- Alexander Thiem
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg
- Paula Romer Roche
- Department of Gynecology, University Hospital Würzburg
- Hemant Joshi
- Department of Gynecology, University Hospital Würzburg
- Dirk Pühringer
- Department of Gynecology, University Hospital Würzburg
- Achim Wöckel
- Department of Gynecology, University Hospital Würzburg
- Joachim E. Diessner
- Department of Gynecology, University Hospital Würzburg
- Manfred Rüdiger
- CatalYm GmbH
- Eugen Leo
- CatalYm GmbH
- Phil F. Cheng
- Department of Dermatology, University of Zurich, University of Zurich Hospital
- Mitchell P. Levesque
- Department of Dermatology, University of Zurich, University of Zurich Hospital
- Matthias Goebeler
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg
- Markus Sauer
- Department of Biotechnology and Biophysics, Julius Maximilians University Würzburg, Am Hubland
- Falk Nimmerjahn
- Division of Genetics, Department of Biology, University of Erlangen
- Christine Schuberth-Wagner
- CatalYm GmbH
- Stefanie von Felten
- oikostat GmbH, Statistical Analyses and Consulting
- Michel Mittelbronn
- Department of Oncology (DONC), Luxembourg Institute of Health (LIH)
- Matthias Mehling
- Department of Biomedicine and Neurology Department, University Hospital Basel
- Andreas Beilhack
- Department of Medicine II, University Hospital of Würzburg
- Sjoerd H. van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center
- Angela Riedel
- Mildred Scheel Early Career Center, University Hospital of Würzburg
- Benjamin Weide
- Department of Dermatology, University Medical Center Tübingen
- Reinhard Dummer
- Forbion
- Jörg Wischhusen
- Department of Gynecology, University Hospital Würzburg
- DOI
- https://doi.org/10.1038/s41467-023-39817-3
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 19
Abstract
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.
