Platelet-Expressed TNFRSF13B (TACI) Predicts Breast Cancer Progression

Abstract

Although treatment options in breast cancer have been improved significantly, predictive biomarkers for disease progression and metastasis are still lacking. Recent studies indicate that several TNF Receptor Superfamily members are involved in breast cancer cell proliferation and survival. Interestingly, TNFRSF13B (TACI) mRNA level were of prognostic relevance in breast cancer patients. In this study we provide evidence for TACI expression on platelets of breast cancer patients. The level of platelet-expressed TACI (pTACI) was significantly increased on platelets derived from breast cancer patients compared to healthy controls. Upon platelet activation, pTACI was downregulated on the platelet surface of healthy donors and breast cancer patients. Of note, inhibition of matrix metalloprotease (MMP) prevented downregulation of pTACI ex vivo, indicating that proteolytic cleavage of pTACI is responsible for reduction of pTACI level. Stimulation of pTACI via BAFF, BAFF 60-mer or APRIL did not influence platelet activation and function. Remarkably, pTACI was particularly regulated during tumor progression in our breast cancer cohort. TACI expression levels on platelets were correlated with clinical parameters including tumor stage, occurrence of metastasis and tumor cell proliferation (Ki67). In conclusion, our data emphasize the potential use of platelets as a liquid biomarker in breast cancer.

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.…”

Controversial Role of the Immune Checkpoint OX40L Expression on Platelets in Breast Cancer Progression

“…Although the expression of several immune checkpoint molecules on platelets has recently been described, their role in cancer is only poorly understood (23)(24)(25). In an effort to further investigate the impact of platelet-expressed immune checkpoints in solid tumors, we characterized the concurrent expression of the three TNF members pGITRL (pTNFSF18), pTACI (pTNFRSF13B), and pOX40L (pTNFSF4) in a cohort of breast cancer patients (Figure 1A).…”

“…Platelets play a critical role in tumor progression, formation of metastasis, tumor immunosurveillance, and immunotherapy via a manifold of mechanisms, including coating of tumor cells, the release of soluble factors, e.g. TGF-ß, VEGF, and expression of immunoregulatory molecules like PD-L1, GITRL, CD40L and TACI (18)(19)(20)(21)(22)(23)(24)(25). Here we show that the immune checkpoint molecule OX40L is frequently expressed on platelets in breast cancer and is negatively correlated with the expression of the immune checkpoint molecules GITRL and TACI on the platelet surface.…”

Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies

“…7 8 In addition, numerous studies demonstrated that elevated platelet counts and expression of certain platelet surface markers are associated with an advanced disease stage and worse outcome. [9][10][11] Platelets mediate tumor cell survival and tumor growth, among others, by secretion or expression of P-selectin, platelet-derived growth factor, vascular endothelial growth factor, and several others. 12 Notably, platelets may also promote tumor immune evasion by impairing natural killer (NK) and T-cell function.…”