TY  - JOUR
AU  - Haake, Markus
AU  - Haack, Beatrice
AU  - Schäfer, Tina
AU  - Harter, Patrick
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
TI  - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-01428
SP  - 4253
PY  - 2023
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.
KW  - Humans
KW  - Mice
KW  - Animals
KW  - T-Lymphocytes: pathology
KW  - Lymphocyte Function-Associated Antigen-1
KW  - Endothelial Cells: pathology
KW  - Immune Checkpoint Inhibitors: pharmacology
KW  - Immune Checkpoint Inhibitors: therapeutic use
KW  - Melanoma: pathology
KW  - Immunotherapy
KW  - Tumor Microenvironment
KW  - Lymphocyte Function-Associated Antigen-1 (NLM Chemicals)
KW  - Immune Checkpoint Inhibitors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37474523
C2  - pmc:PMC10359308
DO  - DOI:10.1038/s41467-023-39817-3
UR  - https://inrepo02.dkfz.de/record/277711
ER  -