Platelet-expressed immune checkpoint regulator GITRL in breast cancer
Open Access
- 4 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 70 (9), 2483-2496
- https://doi.org/10.1007/s00262-021-02866-y
Abstract
Owing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (39090067, 374031971, ZUK 63, MA 8774/1-1, SA1360/7-3, 70112914)
- Mainz Research School of Translational Biomedicine (TransMed)
- Wilhelm Sander-Stiftung (2007.115.3)
- Projekt DEAL
This publication has 42 references indexed in Scilit:
- Increased platelet reactivity in patients with late‐stage metastatic cancerCancer Medicine, 2013
- TGF-β of lung cancer microenvironment upregulates B7H1 and GITRL expression in dendritic cells and is associated with regulatory T cell generationOncology Reports, 2012
- Direct Signaling between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes MetastasisCancer Cell, 2011
- Modulation of Natural Killer Cell Anti-Tumor Reactivity by PlateletsJournal of Innate Immunity, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Valproic acid and all trans retinoic acid differentially induce megakaryopoiesis and platelet-like particle formation from the megakaryoblastic cell line MEG-01Platelets, 2010
- Glucocorticoid-Induced TNFR-Related (GITR) Protein and Its Ligand in Antitumor Immunity: Functional Role and Therapeutic ModulationJournal of Immunology Research, 2010
- Blockade of GITR–GITRL interaction maintains Treg function to prolong allograft survivalEuropean Journal of Immunology, 2010
- Human platelets synthesize and express functional tissue factorBlood, 2007
- Cancer immunoediting by GITR (glucocorticoid‐induced TNF‐related protein) ligand in humans: NK cell/tumor cell interactionsThe FASEB Journal, 2007