TY - JOUR
T1 - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
AU - Haake, Markus
AU - Haack, Beatrice
AU - Schäfer, Tina
AU - Harter, Patrick N.
AU - Mattavelli, Greta
AU - Eiring, Patrick
AU - Vashist, Neha
AU - Wedekink, Florian
AU - Genssler, Sabrina
AU - Fischer, Birgitt
AU - Dahlhoff, Julia
AU - Mokhtari, Fatemeh
AU - Kuzkina, Anastasia
AU - Welters, Marij J.P.
AU - Benz, Tamara M.
AU - Sorger, Lena
AU - Thiemann, Vincent
AU - Almanzar, Giovanni
AU - Selle, Martina
AU - Thein, Klara
AU - Späth, Jacob
AU - Gonzalez, Maria Cecilia
AU - Reitinger, Carmen
AU - Ipsen-Escobedo, Andrea
AU - Wistuba-Hamprecht, Kilian
AU - Eichler, Kristin
AU - Filipski, Katharina
AU - Zeiner, Pia S.
AU - Beschorner, Rudi
AU - Goedemans, Renske
AU - Gogolla, Falk Hagen
AU - Hackl, Hubert
AU - Rooswinkel, Rogier W.
AU - Thiem, Alexander
AU - Roche, Paula Romer
AU - Joshi, Hemant
AU - Pühringer, Dirk
AU - Wöckel, Achim
AU - Diessner, Joachim E.
AU - Rüdiger, Manfred
AU - Leo, Eugen
AU - Cheng, Phil F.
AU - Levesque, Mitchell P.
AU - Goebeler, Matthias
AU - Sauer, Markus
AU - Nimmerjahn, Falk
AU - Schuberth-Wagner, Christine
AU - von Felten, Stefanie
AU - Mittelbronn, Michel
AU - Mehling, Matthias
AU - Beilhack, Andreas
AU - van der Burg, Sjoerd H.
AU - Riedel, Angela
AU - Weide, Benjamin
AU - Dummer, Reinhard
AU - Wischhusen, Jörg
N1 - Funding Information:
This work was supported by the following grants: #B-37 from the Interdisciplinary Centre for Clinical Research (IZKF), Medical Faculty, University of Würzburg, to J.W., #109319 from Deutsche Krebshilfe to J.W., #AZ-1365-18 (Bayerischer Forschungsverbund FORTiTher “Tumordiagnostik für individualisierte Therapie“) from the Bayerische Forschungsstiftung to J.W. (TP1-WP2), #BMBF 01KT2310 TRANSCAN-3 (ERA-NET: Sustained collaboration of national and regional programmes in cancer research—JTC 2021) iParaCyts to J.W., #FKZ031A148 from the German Federal Ministry for Education and Research (BMBF) to M.H. and other team members of J.W., grant #2014-6696 from the Dutch Cancer Society to S.v.d.B. and M.W., European Regional Development Fund (EFRE project) “Center for Personalized Molecular Immunotherapy” to M. Sauer, #FNR PEARL P16/BM/11192868 from the Luxembourg National Research Fond (FNR) to M. Mittelbronn, #TRR305-B02 (Deutsche Forschungsgemeinschaft) to F.N., #TRR201-Z02 (Deutsche Forschungsgemeinschaft) to A.B. We thank the University Research Priority Program (URPP) in translational cancer research at the University of Zurich for funding the biobanking activities at the University of Zurich Hospital. We acknowledge the Department for Transfusion Medicine at the University Hospital Würzburg for providing blood cones, Markus Junker for generating the anti-GDF-15 antibody used in this study, Jens Strelau (Heidelberg, Germany) for having generously provided GDF-15-/-mice used for antibody generation and a GDF-15 expression plasmid, Zsuzsanna Izsvák (Berlin, Germany) for sharing the pT2B-puro Sleeping Beauty transposon vector, Johannes Dietl for institutional support and Sandy Westermann from SCIGRAPHIX for help with preparing the figures. This publication was supported by the Open Access Publication Fund of the University of Würzburg.
Funding Information:
This work was supported by the following grants: #B-37 from the Interdisciplinary Centre for Clinical Research (IZKF), Medical Faculty, University of Würzburg, to J.W., #109319 from Deutsche Krebshilfe to J.W., #AZ-1365-18 (Bayerischer Forschungsverbund FORTiTher “Tumordiagnostik für individualisierte Therapie“) from the Bayerische Forschungsstiftung to J.W. (TP1-WP2), #BMBF 01KT2310 TRANSCAN-3 (ERA-NET: Sustained collaboration of national and regional programmes in cancer research—JTC 2021) iParaCyts to J.W., #FKZ031A148 from the German Federal Ministry for Education and Research (BMBF) to M.H. and other team members of J.W., grant #2014-6696 from the Dutch Cancer Society to S.v.d.B. and M.W., European Regional Development Fund (EFRE project) “Center for Personalized Molecular Immunotherapy” to M. Sauer, #FNR PEARL P16/BM/11192868 from the Luxembourg National Research Fond (FNR) to M. Mittelbronn, #TRR305-B02 (Deutsche Forschungsgemeinschaft) to F.N., #TRR201-Z02 (Deutsche Forschungsgemeinschaft) to A.B. We thank the University Research Priority Program (URPP) in translational cancer research at the University of Zurich for funding the biobanking activities at the University of Zurich Hospital. We acknowledge the Department for Transfusion Medicine at the University Hospital Würzburg for providing blood cones, Markus Junker for generating the anti-GDF-15 antibody used in this study, Jens Strelau (Heidelberg, Germany) for having generously provided GDF-15 mice used for antibody generation and a GDF-15 expression plasmid, Zsuzsanna Izsvák (Berlin, Germany) for sharing the pT2B-puro Sleeping Beauty transposon vector, Johannes Dietl for institutional support and Sandy Westermann from SCIGRAPHIX for help with preparing the figures. This publication was supported by the Open Access Publication Fund of the University of Würzburg. -/-
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7/20
Y1 - 2023/7/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85165405920&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37474523
U2 - 10.1038/s41467-023-39817-3
DO - 10.1038/s41467-023-39817-3
M3 - Article
C2 - 37474523
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4253
ER -