Nature communications · 2023

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

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Haake Markus, Haack Beatrice, Schäfer Tina, Harter Patrick N, Mattavelli Greta, Eiring Patrick, Vashist Neha, Wedekink Florian, Genssler Sabrina, Fischer Birgitt, Dahlhoff Julia, Mokhtari Fatemeh, Kuzkina Anastasia, Welters Marij J P, Benz Tamara M, Sorger Lena, Thiemann Vincent, Almanzar Giovanni, Selle Martina, Thein Klara, Späth Jacob, Gonzalez Maria Cecilia, Reitinger Carmen, Ipsen-Escobedo Andrea, Wistuba-Hamprecht Kilian, Eichler Kristin, Filipski Katharina, Zeiner Pia S, Beschorner Rudi, Goedemans Renske, Gogolla Falk Hagen, Hackl Hubert, Rooswinkel Rogier W, Thiem Alexander, Roche Paula Romer, Joshi Hemant, Pühringer Dirk, Wöckel Achim, Diessner Joachim E, Rüdiger Manfred, Leo Eugen, Cheng Phil F, Levesque Mitchell P, Goebeler Matthias, Sauer Markus, Nimmerjahn Falk, Schuberth-Wagner Christine, von Felten Stefanie, Mittelbronn Michel, Mehling Matthias, Beilhack Andreas, van der Burg Sjoerd H, Riedel Angela, Weide Benjamin, Dummer Reinhard, Wischhusen Jörg

Аннотация

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.

Предметные рубрики MeSH

Humans Mice Animals T-Lymphocytes Lymphocyte Function-Associated Antigen-1 Endothelial Cells Immune Checkpoint Inhibitors Melanoma Immunotherapy Tumor Microenvironment

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH