Abstract
The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors. Since genetic lesions are necessary but not sufficient for Multiple Myeloma (MM) evolution, several authors hypothesized that immune dysfunction involving both B and T cell counterparts plays a key role in the pathogenesis of the disease. The aim of this study is to evaluate the impact of cornerstone treatments for Multiple Myeloma into immune system shaping. A large series of 976 bone marrow samples from 735 patients affected by PCD was studied by flow analysis to identify discrete immune subsets. Treated MM samples displayed a reduction of CD4+ cells (p<0.0001) and an increase of CD8+ (p<0.0001), CD8+/DR+ (p<0.0001) and CD3+/CD57+ (p<0.0001) cells. Although these findings were to some extent demonstrated also following bortezomib treatment, a more pronounced cytotoxic polarization was shown after exposure to autologous stem cell transplantation (ASCT) and Lenalidomide (Len) treatment. As a matter of fact, samples of patients who received ASCT (n=110) and Len (n=118) were characterized, towards untreated patients (n=138 and n=130, respectively), by higher levels of CD8+ (p<0.0001 and p<0.0001, respectively), CD8+/DR+ (p=0.0252 and p=0.0001, respectively) and CD3+/CD57+ cells (p<0.0001 and p=0.0006, respectively) and lower levels of CD4+ lymphocytes (p<0.0001 and p=0.0005, respectively). We demonstrated that active MM patients are characterized by a relevant T cell modulation and that most of these changes are therapy-related. Current Myeloma treatments, notably ASCT and Len treatments, polarize immune system towards a dominant cytotoxic response, likely contributing to the anti-Myeloma effect of these regimens.
Highlights
The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors [1]
The aim of this study is to evaluate the impact of cornerstone treatments for Multiple Myeloma, namely autologous stem cell transplantation (ASCT) and novel agents like bortezomib and lenalidomide, into immune system shaping
In our large series of cases, we demonstrated a relevant therapy related T cell modulation in active Multiple Myeloma patients, with a cytotoxic T cell polarization resulting from Myeloma treatment
Summary
The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors [1]. The pathogenesis of Multiple Myeloma (MM) is a multi-step process in which primary events occurring in the plasma cell are responsible for immortalization and development of a pre-neoplastic condition defined as monoclonal gammopathy of undetermined significance (MGUS). The acquisition of secondary additional events sets the transition to an overt neoplastic and initially asymptomatic condition (smoldering Multiple Myeloma, SMM) and to an active MM (AMM) requiring treatment [2,3,4]. Whole-exome sequencing studies of paired samples from MGUS, SMM and AMM patients demonstrated that most somatic mutations preceded the diagnosis of MM, suggesting that genetic lesions are necessary but not sufficient for the evolution from a pre-neoplastic condition to an overt neoplastic disease [5, 6]. Quantitative and functional alterations involving Natural Killer cells (NK cells), B and T lymphocytes are well known and described in previous studies [8,9,10]
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