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. ABSTRACT: 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 β (TGF-β). 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.