Relationship between Bone Marrow PD-1 and PD-L1 Expression and the Presence of Osteolytic Bone Disease in Multiple Myeloma Patients

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.3183-3183
• Main Authors: Costa, Federica, Bolzoni, Marina, Vescovini, Rosanna, Accardi, Fabrizio, Dalla Palma, Anna Benedetta, De Luca, Federica, Marchica, Valentina, Toscani, Denise, Vicario, Emanuela, Storti, Paola, Aversa, Franco, Giuliani, Nicola
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-118200

Alterations of the bone marrow (BM) immune-microenvironment characterize the progression of monoclonal gammopathies and the development of osteolytic bone disease in multiple myeloma (MM). MM patients exhibit immune dysfunctions as impaired dendritic, NK and T cells, whereas the onset of MM osteolytic lesions is associated to an increased prevalence of Th17 cells. Recently, the pathophysiological role of the programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) pathway together with an increase of myeloid derived suppressor cells (MDSCs) in the induction of tumor tolerance and immune evasion has been underlined with a therapeutic relevance. However, unclear data on the expression profile of PD-1/PD-L1 axis in MM patients have been reported and it is not known if this axis could be related with the presence of osteolytic bone disease. In order to elucidate these aspects, we analyzed a total cohort of 80 consecutives patients with monoclonal gammopathies, including 15 monoclonal gammopathy of undetermined significance (MGUS), 23 smoldering MM (SMM), 21 newly diagnosed MM (MMD) and 21 relapsed/refractory MM (MMR) patients. The presence of bone disease was checked by low-dose computerized tomography (CT) with or without positron emission tomography (PET) scan and by X-rays skeletal survey in 11 MM patients. 87% of MM patients displayed osteolytic lesions. High bone disease (HBD) was defined by the presence of 3 or more osteolytic lesions (62% of our cohort). Patients without bone lesions or with minus of 3 lesions were defined as low bone disease (LBD). BM mononuclear cells were analyzed by flow cytometry, evaluating plasma cells (PCs) (CD138+), monocytes (CD14+) and T cells (total CD3+, CD3+CD4+ and CD3+CD8+). PD-L1 (CD274) expression was evaluated on CD138+ and CD14+ cells, and PD-1 (CD279) on CD3+, CD4+ and CD8+ cells. Lastly, in a subgroup of patients we analysed MDSC populations, including both granulocytic (gMDSCs) (CD11b+HLA-DR-CD14-CD15+) and monocytic MDSCs (mMDSCs), (CD11b+HLA-DR-/lowCD14+CD15-). The percentage of BM CD3+PD-1+ cells increased from MGUS to MMR patients with a significant trend (p=0.004). Indeed, patients with active MM (MMD and MMR) showed both higher % of CD3+PD-1+ cells (median value: 48.5% vs 40.6%, p=0.001) and PD-1 median fluorescence intensity (MFI) on CD3+ (median value: 18.9 vs 16.7 MFI, p=0.024) as compared to patients with SMM and MGUS. CD4+PD-1+, but not CD8+PD-1+ cells are increased in active MM compared to SMM and MG