Immune resistance of Multiple Myeloma: the role of the microenvironment

Immunotherapeutic strategies in Multiple Myeloma are under development. In this thesis we present a new perspective in optimizing immunotherapy in Multiple Myeloma patient. We propose that currently, immunotherapy is limited in efficacy through interactions of Multiple Myeloma cells with the bone marrow microenvironment. This phenomenon was previously only acknowledged as a mechanism of drug resistance. To modulate resistance it is essential to further elucidate these mechanisms. We describe the presence of immune resistance of myeloma cells in the presence of cells of the bone marrow microenvironment and introduce cell adhesion mediated immune resistance (CAM-IR). Furthermore a rational combination of molecularly targeted and immunologic strategy is provided. Next, it is shown that CAM-IR is not restricted to T cell therapy only, but also applicable to antibody therapy. Furthermore we focused on another mechanism of immune escape induced by the microenvironment and show that lysis of myeloma cell by CD4-T cells can be hampered by microenvironment-induced autophagy of myeloma cells. Also Notch is investigated as being one of the targets responsible for the interaction between bone marrow and myeloma cells and thus a possible mechanism for induction of resistance and as a consequence a rational target for therapy. Finally, we investigated targetable mutations in extramedullary myeloma and compared these with the lesions in the bone marrow aiming to identify novel therapeutic targets. In this study we did not identify the mechanisms behind the growth outside the bone marrow, nor the therapy resistance but did demonstrate a high incidence of RAS mutations.

Finally the general discussion is mainly focused on future perspectives on how to improve immunotherapy by interfering with the interactions between myeloma cells and the microenvironment and/ or resistance to apoptosis of myeloma cells; suggestions are provided for rational combinations of immunotherapy and targeted therapies.