GARP-TGFβ Axis on Activated Platelets Supports Tumor Progression

Abstract

Platelet-induced cancer progression is a well-known process driven by mitogenic factors released by activated platelets, among them the most pro-oncogenic is Latent Transforming Growth Factor Beta (LTGFβ). Glycoprotein-A Repetitions Predominant Protein (GARP), a receptor for LTGFβ that enhances its bioactivation, is expressed by regulatory T cells, platelets, and several human cancers. Upon activation platelets dramatically upregulate GARP, suggesting that GARP might play a role in activating LTGFβ released upon platelet degranulation and thus in platelet-induced cancer progression. To address this point we employed a novel mouse model based on the platelet-specific knock-out of the GARP gene. We show that in activated platelets GARP is critical for the expression of surface LTGFβ and for its conversion to the bioactive form. Lack of GARP on platelets, indeed, resulted in the complete absence of serum active TGFβ. To investigate whether GARP plays a role in platelet-induced cancer progression we tested multiple tumor models and observed that genetic deletion of GARP enhanced adoptive T cell therapy of B16 melanoma. We also found that in MC38 colon tumor model GARP on platelets contributes to cancer progression by increasing TGFβ bioavailability, promoting regulatory T lymphocytes and myeloid cells, and favoring the immune evasion of cancer cells. These results demonstrate that platelet-specific deletion of GARP blunted TGFβ activity in the tumor microenvironment and boosted protective immunity against pre-established cancers. We conclude that platelets constrain anti-tumor immunity via a GARP-TGFβ axis and we propose the combination of immunotherapy and platelet inhibitors as a novel treatment strategy against cancer.