Abstract
The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients.
Highlights
Multiple Myeloma (MM) is a malignancy of plasma cells which grow predominantly in the bone marrow (BM)
We demonstrated that oligoclonal expansions not limited to peripheral blood (PB) CD8+ terminal effector CD8+ T cells (TTE) occurred in CD8+ TTE which belong to the pool of marrow infiltrating lymphocytes (MILs) [12]
In this mini-review, in the context of earlier published data, we discussed our recent data which suggest that the host-myeloma escape stage clinically defined by progression from Monoclonal Gammopathy of Unknown Significance (MGUS) to MM is characterized by lessening involvement of Treg in suppressive CD39/CD73 adenosine pathway and development of the regulatory mechanism between BM-resident CD69+ TTE and their circulating CD69- TTE counterpart encompassing oligoclonal expanded TTE
Summary
Multiple Myeloma (MM) is a malignancy of plasma cells which grow predominantly in the bone marrow (BM). The clinical finding of an association between improved clinical outcome and reduced Treg/Th17 ratios [8] or Treg frequency [9, 10] and oligoclonal expansion of terminal effector CD8+ T cells (TTE) [11] suggests Treg and oligoclonal expansion of TTE as key players of immune surveillance in MM This further suggests that T cells may recognize myeloma antigens and differentiate into TTE which are able to exert cytotoxicity against malignant plasma cells through perforin and granzyme expression. The crucial factor, or gatekeeper, which allows for BM-residency of Treg and TTE, and immune surveillance at the site of malignant disease is yet to be determined It is unknown whether BM-residency, per se, is necessary to confer tumor control since the spatial and temporal relationship between circulating and BM-resident T cells and myeloma cells and other cells of the BM microenvironment is not yet elucidated. We postulate that BM-residency of immune cells can be considered as the “Green Card” which allows for permanent myeloma surveillance at the site of disease initiation and progression
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