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

Autor: Haake M; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Haack B; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Schäfer T; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Harter PN; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Neurological Institute (Edinger Institute), University Hospital, Goethe University, Frankfurt/Main, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt/Main, Germany.; Center for Neuropathology and Prion Research, Munich, Ludwig-Maximilians-University, Munich, Germany., Mattavelli G; Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany., Eiring P; Department of Biotechnology and Biophysics, Julius Maximilians University Würzburg, Am Hubland, 97074, Würzburg, Germany., Vashist N; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Wedekink F; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Genssler S; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Fischer B; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Dahlhoff J; Department of Medicine II, University Hospital of Würzburg, Würzburg, Germany., Mokhtari F; Department of Medicine II, University Hospital of Würzburg, Würzburg, Germany., Kuzkina A; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Welters MJP; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands., Benz TM; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Sorger L; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Thiemann V; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Almanzar G; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; Department of Pediatrics, University Hospital Würzburg, Würzburg, Germany., Selle M; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Thein K; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Späth J; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Gonzalez MC; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Reitinger C; Division of Genetics, Department of Biology, University of Erlangen, 91058, Erlangen, Germany., Ipsen-Escobedo A; Division of Genetics, Department of Biology, University of Erlangen, 91058, Erlangen, Germany., Wistuba-Hamprecht K; Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany.; Department of Immunology, University of Tübingen, Tübingen, Germany.; Section for Clinical Bioinformatics, Department of Internal Medicine I, University Medical Center Tübingen, Tübingen, Germany., Eichler K; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Filipski K; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Neurological Institute (Edinger Institute), University Hospital, Goethe University, Frankfurt/Main, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt/Main, Germany., Zeiner PS; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Neurological Institute (Edinger Institute), University Hospital, Goethe University, Frankfurt/Main, Germany.; Frankfurt Cancer Institute (FCI), Frankfurt/Main, Germany.; Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany., Beschorner R; Department of Neuropathology, University of Tübingen, Tübingen, Germany., Goedemans R; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands., Gogolla FH; Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria., Hackl H; Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria., Rooswinkel RW; Forbion, Naarden, The Netherlands., Thiem A; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.; Clinic for Dermatology and Venereology, Rostock University Medical Center, Rostock, Germany., Roche PR; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Joshi H; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.; Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63130, USA., Pühringer D; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Wöckel A; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Diessner JE; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany., Rüdiger M; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Leo E; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Cheng PF; Department of Dermatology, University of Zurich, University of Zurich Hospital, Wagistrasse 18, 8952, Zürich, Switzerland., Levesque MP; Department of Dermatology, University of Zurich, University of Zurich Hospital, Wagistrasse 18, 8952, Zürich, Switzerland., Goebeler M; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany., Sauer M; Department of Biotechnology and Biophysics, Julius Maximilians University Würzburg, Am Hubland, 97074, Würzburg, Germany., Nimmerjahn F; Division of Genetics, Department of Biology, University of Erlangen, 91058, Erlangen, Germany., Schuberth-Wagner C; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., von Felten S; oikostat GmbH, Statistical Analyses and Consulting, Lucerne, Switzerland.; Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, 8001, Zürich, Switzerland., Mittelbronn M; Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.; Luxembourg Centre of Neuropathology (LCNP), Luxembourg, Luxembourg.; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg.; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.; Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Luxembourg, Luxembourg.; Faculty of Science, Technology and Medicine (FSTM), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Mehling M; Department of Biomedicine and Neurology Department, University Hospital Basel, 4031, Basel, Switzerland., Beilhack A; Department of Medicine II, University Hospital of Würzburg, Würzburg, Germany., van der Burg SH; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands., Riedel A; Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany., Weide B; Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany., Dummer R; Forbion, Naarden, The Netherlands., Wischhusen J; Department of Gynecology, University Hospital Würzburg, Würzburg, Germany. Wischhusen_J@ukw.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jul 20; Vol. 14 (1), pp. 4253. Date of Electronic Publication: 2023 Jul 20.
DOI: 10.1038/s41467-023-39817-3
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: