Studies of Plasmacytoid Dendritic Cells in Multiple Myeloma

Abstract

Despite major advances in pharmacotherapy for Multiple Myeloma (MM) it remains incurable. Efforts are underway to develop novel therapeutics which direct the immune system to attack MM or target the supportive stroma to render malignant cells more sensitive to conventional therapy. The knowledge of DC in MM and their potential in such therapies is discussed in this thesis, before focussing on the biology of plasmacytoid dendritic cells (pDC), which are less studied in MM and are the subject of these inquiries. The proposed role for pDC in supporting MM is critically appraised and called into question given their rarity in the tumour niche. However, novel findings are detailed regarding pDC expression in MM of immunoregulatory molecules PD-L1, LAG3, BAFF and AXL, suggesting pDC are in an altered tolerogenic state. A subsequent investigation of novel aspects of human pDC biology produced the first description of the expression, regulation and function of TAM receptors in pDC, definition of the function of CD2 on human pDC, and the first detailed description of functionally distinct human pDC subsets defined by CD2 expression. This resulted in the novel observation that pDC subset balance is regulated by differential apoptosis in stressed conditions, and that glucocorticoids dramatically alter this balance in treated MM patients. MM is associated with a state of complex immune dysregulation and pDC are implicated in this. It will be necessary to address this dysfunction and recognise the effects of anti-MM therapy on immune cells to fully realise the benefit of immune interventions.