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

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.

Inhibition of Dendritic Cell Activation and Modulation of T Cell Polarization by the Platelet Secretome

“…A number of studies have also reported on direct effects of platelets on T cell proliferation and cytokine production (29,51,58). Despite extensive washing, complex formation between platelets and DCs might occur during DC stimulation (13,41).…”

The Dual Role of Platelets in the Cardiovascular Risk of Chronic Inflammation

“…PLTs MPs cultured with Tregs prevented the differentiation into IL-17– and IFN-γ-producing cells in a P-selectin dependent manner ( 104 ). The co-cultures of CD4+ CD25- T cells with PLTs induced Tregs and this effect was abolished by the blocking of glycoprotein A repetitions predominant ( 105 ). In HIV, the aberrant function of CD8+ T lymphocytes was abolished when these cells were co-cultured with PLTs from HD, implying that direct contact with PLTs and TGF-β secretion contributed to this functional improvement ( 117 ).…”

GARP: A Key Target to Evaluate Tumor Immunosuppressive Microenvironment

“…Besides their essential role in hemostasis [52], platelets are involved in angiogenesis, wound healing and immunomodulation [53][54][55]. In cancer, they have been shown to promote tumor invasion [56][57][58][59] and cancer-associated thrombocytosis is an independent poor prognosis factor in multiple cancer types [60][61][62]. Tumors continually activate the coagulation pathways, which leads to thrombin formation and chronic platelet activation.…”

“…Independent of their tumor stage, melanoma patients have shown a significant upregulation of GARP on the platelet surface, compared with healthy donors. Nevertheless, there was no difference in GARP expression between early- and late-stage melanoma patients [ 62 ]. GARP expression was also quantified by flow cytometry in Tregs from PB by Jin et al, but no difference was shown between subjects with lung cancer and healthy subjects [ 17 ].…”