Comparing Heparin and Heparin Mimetics in Targeting Immunomodulatory Proteins from Platelets to Activate T Cell-Dependent Immune Response in Oncology

Platelets play a crucial role in the hematogenous metastasis of cancer. Beyond their mechanical function of forming a protective cloak around circulating tumor cells, which can be antagonized by heparin, activated platelets release various immunomodulatory components. Based on a proteome profiling of releasates, we address the immunosuppressive activities of TGF-β1 and MMP2 to CD4+ and CD8+ T cells in several in vitro assays and compare heparin and synthetic heparin mimetics in targeting them to reverse immunosuppression of platelets in an oncological context. Whole platelet releasates promote the differentiation of naïve human CD4+ T cells into regulatory T cells, while heparin mimetics outperform unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in attenuating this effect. When addressing TGF-β1 as an immunosuppressive component in this CD4+ T cell approach, the lower molecular weight of heparin appears favorable, reflected by higher binding affinities to TGF-β1 in biosensor analyses. The impact of TGF-β1 on reducing the release of cytolytic perforin and granzyme B from CD8+ T cells is reversed by heparin and mimetics in different intensities, favoring smaller molecular sizes. Furthermore, heparin promoted CD8+ T cell binding to activated endothelial cells in a microscopic flow chamber approach in the presence of releasates, indicating increasing CD8+ T cell activity. Additionally, the mimetics significantly reduced the activity of MMP2 compared to LMWH, related to their direct binding and thus deactivating this enzyme. These studies provide insights into immunosuppression of platelets and functional interference thereof by heparin and emphasize heparin mimetics for antagonizing these activities in the context of cancer immunology.