The role of Wnt and mTOR in human memory T cell differentiation

• Applicant: Dr. Godehard Albert Scholz
• Subject Area: Hematology, Oncology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 228875140

Cancer like malignant melanoma is a leading cause of death. A promising treatment strategy is the antigen-specific immunotherapy based on the ability of the immune system to recognize tumor cells as foreign and to form a long-lasting and thereby potent anti-tumor response. Since most terminally differentiated effector T cells are short-lived, the induction of antigen-experienced memory T cells with stem cell-like properties of longevity and self-renewal is essential. Recently, in mice and humans, a multipotent stem cell-like memory CD8+ T cell subset with enhanced survival and anti-tumor activity could be generated by inhibition of glycogen synthase kinase-3ß (GSK-3ß) - a central enzyme in the Wnt signaling pathway. Additionally, it is known that in mice the Wnt pathway effector Tcf-1 plays a key role in memory CD8+ T cell formation. Furthermore, inhibition of the mTOR signaling pathway by rapamycin induces a memory CD8+ T cell subset with augmented anti-tumor efficacy in mice. These findings suggest Wnt and mTOR as promising targets to control memory T cell differentiation.However, current knowledge about the role of Wnt and mTOR in human memory T cell differentiation and the nature of human stem cell-like memory T cells is very limited: Whether mTOR blockade by rapamycin generates a memory CD8+ T cell subset with augmented anti-tumor efficacy in humans as well, whether - apart from rapamycin-sensitive mTORC1 - mTORC2 and the downstream effector Akt are involved in its formation, whether there is a pathway crosstalk between Wnt and mTOR - mediated by GSK-3ß - leading to Tcf-1, whether Wnt and mTOR are also relevant in the induction of human stem cell-like memory CD4+ T cells and, finally, whether stem cell-like memory T cells can be induced by therapeutic vaccination, are the questions addressed in the research proposal. Since stem cell-like memory T cells promise enhanced anti-tumor efficacy, their therapeutic use will be a major step forward in immunology-based cancer therapy.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Pedro Romero