Glycoprotein A repetition predominant (GARP) as a key molecule in the immunosuppressive tumor microenvironment
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Abstract
The immunosuppressive tumor microenvironment (TME) represents a major challenge for effective tumor therapy. Consisting of connective tissue and vessels, immune cells and soluble factors, among others, the TME actively suppresses the antitumor immune response and promotes tumor growth and metastasis.
Glioblastoma (GB) is a highly aggressive brain tumor characterized by great heterogeneity and low survival rates. Despite treatment, recurrence of glioblastoma is almost inevitable. Glioblastoma stem cells (GSC) are the main cause of therapy resistance and tumor recurrence. GSC are characterized by stem cell properties such as unlimited self-renewal, inherent plasticity and high resistance to therapy. Therefore, GSC are the most clinically relevant target for GB therapy, but are difficult to identify due to the lack of universal markers. Therefore, there is an urgent need for new GSC markers and innovative therapeutic approaches targeting specific immunosuppressive pathways in GB.
Glycoprotein A repetitions predominant (GARP), is expressed on the surface of activated regulatory T cells and platelets and has potent immunosuppressive properties. In Zimmer et al, 2019 (manuscript I), the expression of GARP was detected in glioblastomas, low-grade astrocytomas and on the surface of GB cells and GSC. It was shown that GB cells exhibit a strong GARP-mediated immunosuppressive effect and suppress the proliferation of T cells. In Zimmer et al, 2023 (manuscript II), expression of GARP on GSC was demonstrated (1) from different regions of a tumor, (2) with different differentiation and stem cell potential and (3) over the course of therapy. In contrast to other markers such as CD133, the expression of GARP remained stable. Furthermore, GARP was localized in the nucleus and cytoplasm of GB cells, including GSC. This nuclear localization of GARP correlated with poor survival in patients with GB.
However, although GARP was first identified on platelets, more detailed information on the role of GARP on platelets and its interaction with leukocytes during inflammation is limited. In Zimmer et al, 2021 (manuscript III), it was shown that platelets are able to induce regulatory T cells in a GARP-dependent manner (Treg). Cocultures of CD4+ T cells with platelets led to the induction of a regulatory phenotype. In addition, these "platelet-induced" Treg had a significant suppressive capacity. Analysis of platelets from melanoma patients compared to healthy donors showed that patients with stable disease had lower platelet counts compared to patients with progressive disease. In addition, melanoma patients show significantly higher GARP expression on platelets compared to healthy donors.
Overall, GARP was shown to contribute to the immunosuppressive TME, to be a potential complementary marker for the characterization and identification of human GSC and its nuclear localization to be a marker for patient survival. Furthermore, platelets have been shown to induce peripheral Treg via GARP. This is of particular importance with regard to cancer-associated thrombocytosis, where poor prognosis and metastasis are associated with high circulating platelets.