Platelet SYK promotes solid tumor metastasis via TXA2-mediated immunosuppression.

BACKGROUND: Metastasis formation is a multistep process and requires a complex interplay between tumor and host cells. Besides their key role in coagulation and maintaining hemostasis upon injury to vasculature, recent evidence indicates that platelets contribute to cancer progression. OBJECTIVES: However, the molecular mechanisms of platelet activation during metastasis formation is incompletely understood. Here we aim to identify the role of platelet spleen tyrosine kinase (SYK) in the process of solid tumor metastasis. METHODS: To test the role of SYK in platelets, we generated platelet-specific deletion of Syk by crossing PF4-Cre and Sykflox/flox mice to obtain Pf4Cre/+Sykflox/flox animals (referred to as SykΔPlt mice), as well as used SYK-selective inhibitors, such as fostamatinib (R788), entospletinib (GS-9973) and lanraplenib (GS-9876) RESULTS: Based on our results, genetic deletion of Syk in platelets protects mice from metastasis. Administration of malignant melanoma and colorectal adenocarcinoma cells into SYK-deficient platelet-bearing SykΔPlt mice results in significantly less metastatic tumor deposits in the animals compared to wild-type mice. Further, Syk-expressing - but not SYK-deficient - platelets secrete thromboxane A2 (TXA2), that blocks the proliferation and effector function of CD8+ T cells. Pharmacological inhibition of SYK or TXA2 production in platelets results in decreased gastrointestinal tract and lung metastasis formation as well as increased number of CD8+ T cells. CONCLUSIONS: Taken together, our results indicate, that SYK in platelets promotes solid tumor metastasis and tumor immunosuppression. Secretion of TXA2 by platelets is SYK-dependent and can be inhibited by SYK-selective inhibitors, which release anti-tumor CD8+ T cells from TXA2-mediated suppression.