Page 1563 - Hematology_ Basic Principles and Practice ( PDFDrive )

1390 Part VII Hematologic Malignancies

importance of antigen-driven selection in the pathogenesis of MGUS. express programmed death ligand 1 (PDL-1) at variable levels, along
Those researchers investigated the increased association of MGUS in with PDL-1 by cells in bone marrow microenvironment, including
patients with Gaucher disease and showed that the clonal immuno- plasmacytoid dendritic cells (pDCs) and myeloid-derived suppressor
globulin in patients with Gaucher disease was reactive against lyso- cells. These results partly explain the lack of antimyeloma immune
glucosylceramide, which is markedly elevated in these patients. response and provide a rationale for targeting this pathway using
Additionally, 33% of patients with sporadic MGUS also have clonal checkpoint inhibitors.
immunoglobulins specific for the lysolipids and lysophosphatidylcho- Significant B-cell and plasma cell dysfunction is observed in MM
line. These data were confirmed in mouse models of Gaucher as represented by suppressed uninvolved immunoglobulins. For
disease–associated MGUS. Furthermore, these investigators also example, patients with IgA myeloma have suppression of serum IgG
identified a novel type II NKT cell–mediated pathway for and IgM levels. This is not considered to be mediated by high levels
glucosphingolipid-mediated dysregulation of humoral immunity to of monoclonal paraprotein, because suppressed immunoglobulins
account for the increased risk of B-cell malignancies observed in have also been observed in patients with nonsecretory disease. An
Gaucher disease. explanation for this observation remains elusive; however, suppressed
uninvolved immunoglobulins predispose patients to infectious com-
plication because they reduce the patient’s ability to generate a specific
T Cells humoral immune response to infections and/or vaccinations. For
example, in a study of the serologic responses to vaccinations against
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Significant phenotypic and functional aberrations in both CD4 and influenza, Streptococcus pneumoniae, and Haemophilus influenzae in
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CD8 T cells have been observed in patients with both MGUS and 52 patients with MM, researchers reported that only 19% developed
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MM. In MM, impaired action of virus-specific CD8 cells, particu- protective antibody titer levels against influenza, 39% against S.
larly against influenza and Epstein-Barr virus, has been reported. pneumoniae (39%), and 41% against H. influenzae type b. These
Hyperactive T cells associated with impaired T-cell receptor (TCR) observations suggest the necessity to define suitable immunization
signaling and increased sensitivity to costimulatory signals have been protocols for patients with MM and the need to study the humoral
reported. In fact, further abnormalities of the TCR variable β-chain and cellular responses following vaccination in terms of clinical
repertoire have been observed following chemotherapy in patients efficacy, magnitude, and duration of response. Both B- and T-cell
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with MM. Reductions in CD4 T-cell numbers and CD4 /CD8 immune function are also affected by the therapeutic agents them-
T-cell ratio are observed in the peripheral blood of patients with MM. selves with a further increase in the risk of infectious complications,
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Persistent proliferative activity of both CD4 and CD8 T cells has such as the increased risk of herpes zoster virus infection following
been observed in both patients with MGUS and patients with MM. bortezomib treatment or bacterial infections following dexametha-
This activity plays a possible role in controlling tumor cell growth sone use. Recovery of uninvolved immunoglobulins to normal levels
and survival. Overall hyperactivity, clonal expansion, and homeostatic following effective therapy has been associated with both improved
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proliferation of T-cell activity has been observed. Moreover, CD4 survival and protection from infectious complications.
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and CD8 T cells from the bone marrow of patients with MGUS are Alteration in NK cell number has been observed in MM and is
able to mount a stronger immune response against autologous MGUS correlated with disease burden; for example, high numbers of NK
plasma cells than T cells from the bone marrow of patients with MM, cells have been observed in patients with a low tumor burden. NK
suggesting the role of the immune system in controlling plasma cell cells are considered to have a potential therapeutic role, and the
growth in MGUS and loss of immune surveillance in MM. Although immunomodulatory drugs (thalidomide, lenalidomide, and pomalid-
bone marrow T cells are dysfunctional in MM, these cells can be omide) enhance NK cell–mediated cytotoxicity against MM cells.
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stimulated in vitro, leading to restored function. Tregs, the CD4 / Invariant NKT cells, which constitute an innate lymphocyte lineage
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CD25 Th cells, specifically express forkhead box protein Foxp3 and with potential for a potent antitumor immune response through the
actively suppress inappropriate immune responses, maintaining production of Th1 cytokines, are functionally defective in MM;
immune homeostasis. In MM, Tregs are lower in number and are however, these cells can be cultured in vitro with restored function,
dysfunctional, mediated by elevated IL-6, soluble IL-6R, and TGF-β suggesting the possibility of their adoptive transfer as a potential
levels. Another report suggests that, following short exposure to IL-2, therapeutic strategy in MM.
purified Tregs from patients with MM are able to induce suppressive DCs are important antigen-presenting cells that generate effective
activity in vivo and in vitro. Lenalidomide, granulocyte colony- immune responses, including antitumor responses. DC dysfunction
stimulating factor (G-CSF), and allogeneic stem cell transplant may partly mediated by cytokines such as VEGF, IL-10, and TGF-β has
directly or indirectly affect Tregs and may account for some of the been reported in MM. However, it is possible to improve the defec-
observed variations in Treg number and function in patients with tive DC function by in vitro generation. A number of studies have
MM. Th17 cells specifically express the retinoic acid–related orphan used DC-based vaccination strategies, including vaccinations with
receptor-γt and produce IL-17, which provides protection against DCs pulsed with the idiotype protein. DCs pulsed with MM antigen-
certain bacterial, fungal, and viral infections. Development of Th17 directed peptides or MM cell lysate, and fusion of MM cells with
cells is also determined by TGF-β and IL-6, which are upregulated DCs has been reported to lead to an antimyeloma immune responses
in MM. In myeloma, an increased number of Th17 cells have been following vaccination. Increased numbers and function of pDCs have
reported, which is associated with increased serum levels of IL-17 and been reported in the bone marrow microenvironment, which medi-
other proinflammatory cytokines, such as IL-21, IL-22, and IL-23. ates the immune deficiency characteristic of MM and promotes MM
These data support the hypothesis that myeloma cell growth sup- cell growth, survival, and drug resistance. pDCs are resistant to novel
presses immune function and induces osteoclastogenesis, supporting therapies; however, they are being targeted using specific agents,
bone disease in MM. These effects make Th17 cells an important including anti-IL-3R antibody and Toll-like receptors with CpG
therapeutic target in MM. γδ T cells possess a distinct TCR and oligodeoxynucleotides, to both restore pDC immune function and
represent a small subset of T cells that is involved in generating an abrogate pDC-induced MM cell growth.
antimyeloma response. γδ T cells are considered a bridge between
innate and adaptive immunity and are able to kill major histocompat-
ibility complex class I chain–related protein A (MICA)-positive MM CLINICAL MANIFESTATIONS
cells via the NKG2D (an NK cell–triggering receptor) pathway.
Interestingly, MICA expression is significantly higher in plasma cells Patients with MM present with a number of signs and symptoms that
from patients with MGUS. Bisphosphonates have been shown to are related to either marrow infiltration by plasma cells or manifesta-
activate γδ T cells, which may in part explain their weak antimyeloma tions of end-organ damage leading to renal dysfunction, bone lesions,
activity. As in other malignancies, expression of PD-1 is increased in and/or immunoparesis (Table 86.4). However, in up to 20% of the
T cells from patients with active myeloma. Moreover, myeloma cells patients, MM may present with asymptomatic disease diagnosed on