Defining the role of CD8+ regulatory T cells in Graft-versus-Host Disease after allogeneic stem cell transplantation.

• Applicant: Dr. Tobias Holderried
• Subject Area: Hematology, Oncology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438201081

Cancer immunity mediated by the adaptive immune system in various solid and hematological malignancies has gained traction in the last decade. Various approaches to enhance and activate anti-tumor immunity have led to tremendous advances in cancer treatment. Humoral and cellular immunosuppression in the tumor-microenvironment, however, have a major impact on tumor behavior in solid and hematologic malignancies by allowing tumor escape, impairing the anti-tumor response in patients and constricting the success of immunotherapeutic options. In contrast, regulatory mechanisms have beneficial effects on the development/treatment of Graft-versus-Host Disease after allogeneic stem-cell transplantation. Recent studies have demonstrated the contribution of T cell-mediated immune regulation mainly focusing on CD4+CD25+FoxP3+ regulatory T cells (CD4+ Treg), but also showing regulatory activity of subsets of B and natural killer cells as well as myeloid derived suppressor cells.The mechanisms of CD8+ regulatory T cell (CD8+ Treg) function in tumor immunity and during immune reconstitution after allogeneic stem cell transplantation, however, remain elusive until now. Recently a novel CD8+ Treg subset has been identified in mice, which represents ~5% of CD8+ T cells and is characterized by expression of the CD44+CD122+Ly49+Helios+ phenotype. This T cell subset is critical to maintain self-tolerance and plays major roles in anti-viral immunity and anti-tumor effects. Additionally, preliminary results suggest regulatory activity of CD8+ Treg after allogeneic stem cell transplantation.The objectives of this proposal are 1) to validate the suppressive mechanisms of murine CD8+ Treg in Graft-versus-Host Disease (GvHD) and 2) to determine the functional relevance of human CD8+ Treg for the development of human GvHD after allogeneic stem cell transplantation. To interrogate the inhibitory effects of CD8+ Treg in GvHD in vivo a well-established acute mouse model will be used. This knowledge will be used to assess human CD8+ Treg and evaluate their impact on acute and chronic GvHD in patients after allogeneic stem-cell transplantation. These studies, if successful, will open a new avenue for the development of novel immunotherapeutic strategies for the prevention and/or treatment of patients with GvHD.

• DFG Programme: Research Grants