Platelet-expressed immune checkpoint regulator GITRL in breast cancer

Abstract

Owing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.

Platelet-Expressed TNFRSF13B (TACI) Predicts Breast Cancer Progression

“…This confirms and extends current knowledge on the expression and specific regulation of TNF(R)SF members on platelets, which is so far mainly focused on the role of platelet-derived ligands, e.g. RANKL, GITRL, CD40L, FasL, TRAIL (17,20,(37)(38)(39)(40). Expression/modulation of platelet proteins in general and of pTACI in particular may be a result of (a) (altered) translation during megakaryopoiesis, (b) trogocytosis which has been reported upon tumor cell/platelet interaction (41) or (c) de novo protein biosynthesis in platelets, which can among others occur from ingested, tumor-derived mRNA (25).…”

Regulation of Platelet-Derived ADAM17: A Biomarker Approach for Breast Cancer?

“…A high inter-donor variability was observed, particularly in tumor patients, which might reflect certain “malignant platelet phenotypes” associated with distinct disease characteristics [ 26 , 27 ]. As expression and activity of various proteins on the platelet surface reportedly are influenced by platelet activation [ 28 , 29 , 30 , 31 , 32 ], we explored whether pADAM17 is also regulated by this process. In breast cancer patients, ADAM17 expression on the surface of activated platelets was lower compared with resting (CD62P-negative) platelets and pADAM17 downregulation was positively related to basal ADAM17 expression on resting platelets, which may indicate that pADAM17 expression is regulated upon platelet activation in the context of breast cancer.…”

Bidirectional Interaction Between Cancer Cells and Platelets Provides Potential Strategies for Cancer Therapies

“…Platelet-derived GITRL (217) and RANKL (216) both induced NK cell inhibition via interacting with their specific receptors on NK cells (GITR, RANK, respectively). Recently, Zhou et al showed that GITRL overexpression of platelets was substantially associated with tumor-derived soluble factors such as TGFb (215). These studies prove that platelets boost CTCs' survival in the process of hematogenous metastasis by suppressing innate and adaptive immunity.…”

“…As a result, tumor cells were protected from NK cell recognition and cytotoxicity ( 213 ). Immunomodulatory TNF family members, such as glucocorticoid-induced TNF receptor-related ligand (GITRL) ( 215 ), receptor activator of NF-κB ligand (RANKL) and Oxford 40 ligand(OX40L) were upregulated in activated platelets from cancer patients, indicating that they were possibly involved in tumor pathophysiology ( 216 ). Platelet-derived GITRL ( 217 ) and RANKL ( 216 ) both induced NK cell inhibition via interacting with their specific receptors on NK cells (GITR, RANK, respectively).…”