GARP as an Immune Regulatory Molecule in the Tumor Microenvironment of Glioblastoma Multiforme.

Zimmer Zimmer,Tuettenberg Tuettenberg,Leukel Leukel,Sommer Sommer,Sprang Sprang,Kim Kim,Ringel Ringel,Khafaji Khafaji

doi:10.3390/ijms20153676

Abstract

Glycoprotein A repetition predominant (GARP), a specific surface molecule of activated regulatory T cells, has been demonstrated to significantly contribute to tolerance in humans by induction of peripheral Treg and regulatory M2-macrophages and by inhibition of (tumorantigen-specific) T effector cells. Previous work identified GARP on Treg, and also GARP on the surface of several malignant tumors, as well as in a soluble form being shedded from their surface, contributing to tumor immune escape. Preliminary results also showed GARP expression on brain metastases of malignant melanoma. On the basis of these findings, we investigated whether GARP is also expressed on primary brain tumors. We showed GARP expression on glioblastoma (GB) cell lines and primary GB tissue, as well as on low-grade glioma, suggesting an important influence on the tumor micromilieu and the regulation of immune responses also in primary cerebral tumors. This was supported by the finding that GB cells led to a reduced, in part GARP-dependent effector T cell function (reduced proliferation and reduced cytokine secretion) in coculture experiments. Interestingly, GARP was localized not only on the cell surface but also in the cytoplasmatic, as well as nuclear compartments in tumor cells. Our findings reveal that GARP, as an immunoregulatory molecule, is located on, as well as in, tumor cells of GB and low-grade glioma, inhibiting effector T cell function, and thus contributing to the immunosuppressive tumor microenvironment of primary brain tumors. As GARP is expressed on activated Treg, as well as on brain tumors, it may be an interesting target for new immunotherapeutic approaches using antibody-based strategies as this indication.

Highlights

Glioblastomas (GBs) are characterized by a aggressive behavior, including infiltrating tumor cells in the surrounding brain tissue
We have recently shown that the specific Treg activation marker Glycoprotein A repetition predominant (GARP) in its soluble form has tolerance-inducing functions [18]
GARP has been detected on melanoma cells, as well as on brain metastasis of melanoma [21]

Summary

Introduction

Glioblastomas (GBs) are characterized by a aggressive behavior, including infiltrating tumor cells in the surrounding brain tissue. Tumor cells are able to suppress immune responses through regulatory cells such as microglial cells or invading regulatory T cells, especially in the relapse situation [1,2,3]. Very little is known about the factors influencing the immigration of immune cells, as well as an effective immune response, in the tumor milieu of primary brain tumors such as GB, both in the primary tumor tissue and in the recurrent tissue. In many tumor entities, active suppression of the immunological defense in tumor patients significantly limits the success, in particular of immunotherapies [4]. In addition to general immunological tolerance mechanisms through regulatory T cells or tolerogenic dendritic cells (tolDC), the tumor itself develops immune escape mechanisms. By generating an inhibitory micromilieu, efficient antitumor responses are switched off or prevented, limiting the effectiveness of immunotherapeutic approaches

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Results

Conclusion