Project Details
Projekt
Targeting immune escape mechanisms to eliminate persisting MPN cells
Applicant
Professor Dr. Robert Zeiser
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983
Myeloproliferative neoplasms (MPN) often respond well to symptomatic therapy. However, this therapy fails to eliminate the malignant clone, resulting in disease persistence as the major clinical challenge. We propose here that persistence is mediated by immune escape both through the expression of immune-inhibitory molecules on the cell surface of MPN cells, which prevent immune-mediated elimination and the release of TGF-β. Our preliminary data indicate that activating calreticulin (CALR) mutations can cause the expression of TGF-β. To clarify the functional relevance of TGF-β in vivo we analyzed mice carrying Calrdel52MPL BM. We observed an improved survival of the mice upon TGF-β neutralization. Therefore, the goal is to develop immuno-therapeutic approaches interfering with immuno-suppressive factors and thereby promoting elimination of persisting MPN cells. In a first aim we will clarify which checkpoint molecules and soluble inhibitory factors are increasingly expressed by myeloid cells upon acquisition of an activating CALR mutation. Here we will use metabolomics of the CALR vs empty vector cells. In a second aim we will analyze how the signaling pathways activated by the CALR mutation lead to activation of the promoters of checkpoint molecules, to TGF-β release and to metabolic alterations that cause LA release and persistence of MPN clones. In a third aim we will assess which immuno-therapeutic approaches that promote elimination of persisting MPN cells can be used therapeutically. The overall goal is to develop immuno-therapeutic approaches interfering with immuno-suppressive ligands, metabolites and TGF-β, thereby promoting elimination of persisting MPN cells.
DFG Programme
Research Units
