Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3716274

Documents

In Collections

This item can be found in the following collections:

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

Article / Letter to editor
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...Show more 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.
Show less
All authors
Haake, M.; Haack, B.; Schäfer, T.; Harter, P.N.; Mattavelli, G.; Eiring, P.; Vashist, N.; Wedekink, F.; Genssler, S.; Fischer, B.; Dahlhoff, J.; Mokhtari, F.; Kuzkina, A.; Welters, M.J.P.; Benz, T.M.; Sorger, L.; Thiemann, V.; Almanzar, G.; Selle, M.; Thein, K.; Späth, J.; Gonzalez, M.C.; Reitinger, C.; Ipsen-Escobedo, A.; Wistuba-Hamprecht, K.; Eichler, K.; Filipski, K.; Zeiner, P.S.; Beschorner, R.; Goedemans, R.; Gogolla, F.H.; Hackl, H.; Rooswinkel, R.W.; Thiem, A.; Roche, P.R.; Joshi, H.; Pühringer, D.; Wöckel, A.; Diessner, J.E.; Rüdiger, M.; Leo, E.; Cheng, P.F.; Levesque, M.P.; Goebeler, M.; Sauer, M.; Nimmerjahn, F.; Schuberth-Wagner, C.; Felten, S. von; Mittelbronn, M.; Mehling, M.; Beilhack, A.; Burg, S.H. van der; Riedel, A.; Weide, B.; Dummer, R.; Wischhusen, J.
Date
2023-07-20
Journal
Nature Communications
Volume
14
Issue
1
DOI
doi:10.1038/s41467-023-39817-3
Link
https://www.nature.com/articles/s41467-023-39817-3