Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.
Markus HaakeBeatrice HaackTina SchäferPatrick N HarterGreta MattavelliPatrick EiringNeha VashistFlorian WedekinkSabrina GensslerBirgitt FischerJulia DahlhoffFatemeh MokhtariAnastasia KuzkinaMarij J P WeltersTamara M BenzLena SorgerVincent ThiemannGiovanni AlmanzarMartina SelleKlara TheinJacob SpäthMaria Cecilia GonzalezCarmen ReitingerAndrea Ipsen-EscobedoKilian Wistuba-HamprechtKristin EichlerKatharina FilipskiPia S ZeinerRudi BeschornerRenske GoedemansFalk Hagen GogollaHubert HacklRogier W RooswinkelAlexander ThiemPaula Romer RocheHemant JoshiDirk PühringerAchim WöckelJoachim E DiessnerManfred RüdigerEugen LeoPhil Fang ChengMitchell Paul LevesqueMatthias GoebelerMarkus SauerFalk NimmerjahnChristine Schuberth-WagnerStefanie von FeltenMichel MittelbronnMatthias MehlingAndreas BeilhackSjoerd H van der BurgAngela RiedelBenjamin WeideReinhard DummerJörg WischhusenPublished in: Nature communications (2023)
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.
Keyphrases
- endothelial cells
- ejection fraction
- newly diagnosed
- prognostic factors
- stem cells
- dna damage
- patient reported outcomes
- clinical trial
- staphylococcus aureus
- mouse model
- cell cycle
- cell proliferation
- transcription factor
- pseudomonas aeruginosa
- bone marrow
- mesenchymal stem cells
- cystic fibrosis
- biofilm formation
- candida albicans
- basal cell carcinoma