Treatment Induced Cytotoxic T-Cell Modulation in Multiple Myeloma Patients

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.

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma

“…Impairment of naïve T cells reduces the TCR repertoire clonality 36,43 , which typically is associated with worse outcomes in various malignancies 44,45 . Therapies that stress the immune environment, including many of the immunotherapies used for MM, such as IMiDs and ASCT, can also drive similar alterations 46,47 , which in the elderly may be slow to recover due to impairment of new naïve T cell reconstitution 36,38,39 . Cytotoxic cells are critical for clearing the malignant populations; however, the accumulation of these differentiated T cell populations may reflect a less reactive T cell compartment.…”

Normalization of the Immunological Microenvironment and Sustained Minimal Residual Disease Negativity: Do We Need Both for Long-Term Control of Multiple Myeloma?

“…In general, all novel agents not only target malignant PCs, but also potentially polarize the immune system from an immunosuppressive state towards cytotoxic behavior (see Figure 3) [100].…”

“…In general, all novel agents not only target malignant PCs, but also potentially polarize the immune system from an immunosuppressive state towards cytotoxic behavior (see Figure 3) [100]. MAbs target neoplastic cells and activate the immune system or disrupt a signaling pathway protecting neoplastic cells from immune-cell destruction [120].…”

T cell landscape and dynamics in immunoglobulin light chain amyloidosis before and after daratumumab‐based therapy

“…Different from other types of plasma cell dyscrasia such as multiple myeloma (MM) and its precursor stage of monoclonal gammopathy of undetermined significance (MGUS) that have well‐characterized numerical and functional alterations in T, natural killer (NK) cells, monocytes/macrophages, and dendritic cells, not much is known of the changes of these cells in AL. 8 , 9 Recently, high counts of monocytes and reduced frequencies of NK cells in peripheral blood were found in AL patients and the circulating monocyte counts were associated with an increased risk for AL. 10 , 11 The changes in T cells, however, are not clear.…”

“… 14 An elevation of CD8 + T and a reduction of CD4 + T cell frequencies in the BM were observed in MM patients treated with bortezomib, lenalidomide or autologous stem cell transplantation. 9 Whether these treatments lead to similar changes in patients with AL has not been directly examined.…”