Platelet-Derived GARP Induces Peripheral Regulatory T Cells-Potential Impact on T Cell Suppression in Patients with Melanoma-Associated Thrombocytosis.

Simple Summary Thrombocytosis correlates with poor prognosis for treatment of malignant melanoma. Detailed information on how platelets modify the anti-tumoral immune response is still elusive. Analyzing the immunomodulatory capacities of platelets on huCD4(+) T cells in vitro, we were able to show that platelets are able to induce regulatory T cells by the expression of glycoprotein A repetitions predominant (GARP), thus indicating a potential contribution to the immunosuppressive tumor microenvironment. Furthermore, we analyzed platelets of melanoma patients in stage I and IV. Melanoma patients with poor prognosis showed, besides an increased platelet count, a significant increase in GARP expression on platelets. This study suggests the contribution of platelets on the immune evasion in melanoma patients, opening a new potential way to target the immunosuppressive TME. Platelets have been recently described as an important component of the innate and adaptive immunity through their interaction with immune cells. However, information on the platelet-T cell interaction in immune-mediated diseases remains limited. Glycoprotein A repetitions predominant (GARP) expressed on platelets and on activated regulatory T cells (Treg) is involved in the regulation of peripheral immune responses by modulating the bioavailability of transforming growth factor beta (TGF-beta). Soluble GARP (sGARP) exhibits strong regulatory and anti-inflammatory capacities both in vitro and in vivo, leading to the induction of peripheral Treg. Herein, we investigated the effect of platelet-derived GARP on the differentiation, phenotype, and function of T effector cells. CD4(+)CD25(-) T cells cocultured with platelets upregulated FoxP3, the master transcription factor for Treg, were anergic, and were strongly suppressive. These effects were reversed by using a blocking anti-GARP antibody, indicating a dependency on GARP. Importantly, melanoma patients in different stages of disease showed a significant upregulation of GARP on the platelet surface, correlating to a reduced responsiveness to immunotherapy. In conclusion, our data indicate that platelets induce peripheral Treg via GARP. These findings might contribute to diseases such as cancer-associated thrombocytosis, wherein poor prognosis and metastasis are associated with high counts of circulating platelets.