Phd in IINNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Thesis title: Role of Bone Marrow Stromal Cells in the Regulation of NKG2D and DNAM-1 Ligand Expression on Multiple Myeloma Cells

Multiple myeloma (MM) is a haematological cancer characterized by an abnormal proliferation of malignant plasma cells in the bone marrow (BM). BM stromal cells (BMSCs) strongly contribute to MM progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. Natural Killer (NK) cells are cytotoxic lymphocytes involved in the control of MM. The engagement of NKG2D and DNAM-1 activating receptors plays an important role in NK cell-mediated recognition and killing of MM cells. Indeed, malignant plasma cells can express NKG2D ligands, MICA/B and ULBPs and DNAM-1 ligands, PVR and Nectin-2. Here, we analyzed the role of MM patient-derived BMSCs in the regulation of the expression of these molecules. We found that BMSCs enhance MICA and PVR surface expression on MM cells and promote their NK cell-mediated recognition. MICA and PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked MICA and PVR upregulation. IL-8 mainly associated with the surface of stromal microvesicles (MVs) mediates PVR upregulation via CXCR1/CXCR2 signaling activation. Instead, MICA expression is regulated by Gas6/TAM signaling pathway. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of MICA and PVR expression in cancer cells.