Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma

Abstract

BackgroundRegulatory T (Treg) cells play an important role in the maintenance of immune system homeostasis. Multiple myeloma (MM) is a plasma cell disorder frequently associated with impaired immune cell numbers and functions.MethodsWe analyzed Treg cells in peripheral blood (n = 207) and bone marrow (n = 202) of pre-malignant and malignant MM patients using flow cytometry. Treg cells and their subsets from MM patients and healthy volunteers were functionally evaluated for their suppressive property. A cohort of 25 patients was analyzed for lymphocytes, CD4 T cells and Treg cells before and after treatment with cyclophosphamide, thalidomide plus dexamethasone (CTD).ResultsWe found elevated frequencies of Treg cells in newly diagnosed (P<0.01) and relapsed MM patients (P<0.0001) compared to healthy volunteers. Also, Treg subsets including naïve (P = 0.015) and activated (P = 0.036) Treg cells were significantly increased in MM patients compared to healthy volunteers. Functional studies showed that Treg cells and their subsets from both MM and healthy volunteers were similar in their inhibitory function. Significantly increased frequencies of Treg cells were found in MM patients with adverse clinical features such as hypercalcemia (>10 mg/dL), decreased normal plasma cell (≤5%) count and IgA myeloma subtype. We also showed that MM patients with ≥5% of Treg cells had inferior time to progression (TTP) (13 months vs. median not reached; P = 0.013). Furthermore, we demonstrated the prognostic value of Treg cells in prediction of TTP by Cox regression analysis (P = 0.045). CTD treatment significantly reduced frequencies of CD4 T cells (P = 0.001) and Treg cells (P = 0.018) but not Treg cells/CD4 T cells ratio compared to pre-treatment.ConclusionsOur study showed immune deregulation in MM patients which is evidenced by elevated level of functionally active Treg cells and patients with increased Treg cells have higher risk of progression.

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…These observations are in accordance with observations made in several other malignancies [56], and suggest that MM cells evade immune surveillance partially through the increase of suppressive Tregs [60]. The myeloma-promoting role of Tregs is reinforced by observations in MM patients showing a shorter survival for patients with high Treg percentages [50] and indicating that the number of Tregs is a predictive marker for the risk of disease progression [60]. The finding that MM cells are able to induce the generation of Tregs in vitro further corroborates these results [61].…”

“…Initially, a decrease in Treg numbers was reported in MM patients, along with a defect in their ability to suppress T-cell proliferation [57]. In contrast, several more recent studies have concluded that the number of functionally intact Treg is increased in MM patients [49,50,[58][59][60]. These observations are in accordance with observations made in several other malignancies [56], and suggest that MM cells evade immune surveillance partially through the increase of suppressive Tregs [60].…”

“…In contrast, several more recent studies have concluded that the number of functionally intact Treg is increased in MM patients [49,50,[58][59][60]. These observations are in accordance with observations made in several other malignancies [56], and suggest that MM cells evade immune surveillance partially through the increase of suppressive Tregs [60]. The myeloma-promoting role of Tregs is reinforced by observations in MM patients showing a shorter survival for patients with high Treg percentages [50] and indicating that the number of Tregs is a predictive marker for the risk of disease progression [60].…”

Suppression of the noninvolved pair of the myeloma isotype correlates with poor survival in newly diagnosed and relapsed/refractory patients with myeloma

“…Tregs have been attributed to suppress immunoglobulin production and secretion without affecting proliferation of the myeloma cells 20, a phenomenon which has been found to be isotype specific 21, 22. Tregs suppress antitumor cytotoxicity 23, and increased Tregs levels have been linked with shorter survival in various cancers 24 and in multiple myeloma 19, 25. More specifically, increased Treg levels in myeloma were found to correlate with low polyclonal plasma cell numbers, adverse clinical features and shorter survival 25.…”

“…Tregs suppress antitumor cytotoxicity 23, and increased Tregs levels have been linked with shorter survival in various cancers 24 and in multiple myeloma 19, 25. More specifically, increased Treg levels in myeloma were found to correlate with low polyclonal plasma cell numbers, adverse clinical features and shorter survival 25. Accordingly, in multiple myeloma patients with long standing disease control and survival, significantly lower numbers of Tregs were found compared to patients with active disease 26, 27.…”