Project Details
Projekt
T cell interactions within the multiple myeloma niche
Applicant
Professor Dr. Andreas Beilhack
Subject Area
Hematology, Oncology
Term
from 2014 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 179902948
The bone marrow protects and nurtures hematopoietic stem cells, long-lived plasma cells and memory T cells but also shelters malignant plasma cell proliferation in multiple myeloma (MM). MM causes significant morbidity and mortality and remains incurable with standard therapies, yet autologous or allogeneic hematopoietic cell transplantation may result in long-term disease remission or even cure in some patients. These beneficial anti-myeloma effects are ascribed in part to the immunological effects of the graft. Yet, the underlying mechanisms and essential graft components have remained elusive. Here, we test the hypothesis that T cell interactions with myeloma cells and the adjacent stroma contribute to the process of myeloma bone disease and serve as potential therapeutic targets. Conversely, it remains elusive how the MM niche impacts T cell function. Thus, we will address the following specific aims: (I) To investigate the direct in vivo interactions of defined CD4+ and CD8+ T cell subsets with MM cells within the MM niche. (II) To study the reciprocal interactions of defined T cell subsets with MM niche defining cell populations, such as CXCL12+ stromal cells, mesenchymal stem cells, osteoblasts, osteoclasts and endothelium. (III) To evaluate the therapeutic potential of modulating T cell migration and effector functions to deprive MM of essential niche interactions. To achieve these aims, we have established models of orthotopic syngeneic and humanized MM, adoptive cell transfers, and advanced microscopy techniques (e.g. high-resolution 3D light-sheet fluorescence microscopy). Imaging and microscopy will direct further cellular (e.g. multi-parameter flow cytometry, functional in vitro assays) and molecular in vitro analyses. Our studies will help to refine therapeutic interventions, in particularly immunotherapy of MM bone disease.
DFG Programme
Research Units
