scholarly journals The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterisation of immune status in multiple myeloma

2012 ◽  
Vol 106 (3) ◽  
pp. 546-552 ◽  
Author(s):  
K Giannopoulos ◽  
W Kaminska ◽  
I Hus ◽  
A Dmoszynska
Keyword(s):  
Multiple Myeloma ◽  
T Regulatory Cells ◽  
Immune Status ◽  
Regulatory Cells

scholarly journals Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Reverse Immunosuppression in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2106-2106 ◽  
Author(s):  
Xiaoyan Feng ◽  
Chirag Acharya ◽  
Gang An ◽  
Kenneth Wen ◽  
Li Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
T Regulatory Cells ◽  
T Cell Subsets ◽  
Cell Contact ◽  
Dependent Manner ◽  
Regulatory Cells ◽  
Advisory Committees ◽  
Equity Ownership ◽  
And Function

Abstract We here study targeting CD38 to overcome immunosuppression by CD4+CD25highFoxp3+ T regulatory cells (Tregs) in multiple myeloma (MM). CD38 is differentially expressed on T cell subsets with higher levels on Tregs than CD4+CD25- conventional T cells (Tcons) from MM patients vs. normal donors. CD38 levels and the percentages of CD38high Tregs are further increased by low doses of Pomalidomide (Pom) or Lenalidomide (Len), which could confer further sensitivity to CD38 targeting. This result further support combined targeting CD38 with immunomodulatory drugs (IMiDs) to mitigate tumor-related immunosuppression. Importantly, anti-CD38 mAb SAR650984 (SAR) preferentially decreases Treg while increases Tcon frequencies, which is enhanced by Pom/Len. SAR induces apoptosis and inhibits proliferation of Tregs in Fc-independent manner. It further reduces Foxp3 and IL10 in Tregs, blocks migration of Tregs, and restores proliferation and function of Tcons. Importantly, SAR augments MM cell lysis by CD8+ T and natural killer cells, as seen by enhanced cell surface CD107a for degranulation and IFNγ production. Pom/Len further enhances these effector functions induced by SAR. Ex vivo cocultures of MM cells with peripheral blood mononuclear cells (PBMCs) or Tcons significantly induce Tregs (iTregs) which express even higher CD38 than natural occurring Tregs (nTregs) in a time-dependent manner. CD38 is increased at even higher extent on iTregs induced from Tcons than PBMCs when cocultured with MM cells, indicating the conversion of Tcons into iTregs. This is associated with elevated circulating CD38+ Tregs in MM patients vs. normal donors. Besides upregulated CD38, iTregs, when compared with Tcons alone, express higher levels of CD25, Foxp3, CD44, ICOS, and PD1, while low CD127. PDL1 is concurrently increased on MM cell membrane in these cocultures. Since anti-TGFb, -PD1, or -PDL1 mAb, when added alone, partially blocks iTreg induction from Tcon, cell-cell contact via PD1/PDL1 interaction and TGFb are attributed to induction of iTregs. SAR decreases MM cell- and bone marrow stromal cell-induced iTregs and production of inhibitory cytokines TGFb and IL10, further indicating that SAR targets immunosuppressive function in CD38high iTregs. Finally, CD38 levels correlate with differential inhibition by SAR on Tregs from MM vs normal donors. Taken together, these results show that targeting CD38 can preferentially block potent immunosuppressive Tregs while restore effector function to further against MM. Disclosures Anderson: Oncoprep: Equity Ownership; Acetylon: Equity Ownership; C4 Therapeutics: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

The Frequency of T Regulatory Cells Modulates the Survival of Multiple Myeloma Patients: Detailed Characterization of Immune Status In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 984-984
Author(s):  
Krzysztof Giannopoulos ◽  
Wioletta Kaminska ◽  
Anna Dmoszynska
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Immune System ◽  
Dendritic Cell ◽  
Immune Cells ◽  
T Regulatory Cells ◽  
Control Group ◽  
Regulatory Cells ◽  
Cell Antigen ◽  
Blood Dendritic Cell

Abstract Abstract 984 Multiple myeloma (MM) is a immunoproliferative disease which is characterized by the uncontrolled proliferation of plasma cells which is accompanied by defects in the immune system. Abnormalities of function and number of T regulatory cells (Treg), dendritic cells (DC) might be responsible for the immunosuppression in MM. DC and Treg are the most important cells in the immune system, able to control peripheral tolerance as well as response to foreign and tumor antigens. The current study aimed to characterize the frequency of Treg, DC as well as subpopulations of T cells bearing regulatory properties like CD4+GITR+, CD4+CD62L+, CD3+TCRγδ+ along with the concentration of IL-10, TGFβ, IL-6 in patients with MM. Subsequently the influence of therapy on those components of immune system was assessed. The study population consisted of 66 newly diagnosed MM patients (females-29, males-37, median age 66.5 years; range 39–81) admitted to the Department of Hematoonocology Medical University of Lublin. The study was approved by the Local Ethics Committee. Immune cells subpopulations were evaluated by the flow cytometry. Myeloid DC (MDC) were identified as blood dendritic cell antigen-1 (BDCA-1) positive and CD19 negative cells. Plasmacytoid DC (PDC) were characterized as blood dendritic cell antigen-1 (BDCA-2) and CD123 positive cells. We also estimated the frequency of Treg (CD4+CD25hiFOXP3+) and other populations of lymphocytes with regulatory function such as: CD4+GITR+, CD4+CD62L+, CD3+TCRγδ+. We used enzyme linked (ELISA) assay to detect cytokines IL-10, IL-6, TGFβ in serum of MM patients. In the current study we observed that the percentage of both MDC and PDC was lower in MM compared to control group (0.16% vs. 0.19% and 0.03% vs. 0.12%, respectively). The frequency of Treg was significantly higher in MM patients compared to healthy control (6.16% vs 0.05%). Also, the percentages of CD4+GITR+, CD4+CD62L+ were increased compared to healthy volunteers (95.19% vs 78% and 10.35% vs 0.42%, respectively). The frequency of CD3+TCRγδ+ was lower compared to control group (2.82% vs 6.05%). We further assessed the influence of certain immune cells frequencies on clinical behavior of MM patients. We found that patients with higher percentages of Treg live shorter (median survival 21 months vs not-reached, p=0.013, Figure 1). Serum levels of cytokines IL-10, IL-6, TGFβ were increased in MM compared to control group (1.16pg/mL vs 0.91pg/mL for IL-10; 3.74pg/mL vs 2.12pg/mL for IL-6; 32233.5pg/mL vs 3877.23pg/mL for TGFβ). During therapy we detected significant lowering concentration of IL-10, to higher extent in responders. In conclusion our results identified several abnormalities of immune system in MM. The dysfunction of immune system (decreased antigen presentation along with increased frequencies of suppressive cells and cytokines) might facilitate progression of the disease and infectious complications. The most important finding of our study is the key function of Treg in modulation of overall survival of MM patients. Overall survival by low (Treg low – below the median) and high (Treg hi – above the median) T regulatory cells frequencies of multiple myeloma patients. Disclosures: No relevant conflicts of interest to declare.

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

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e47077 ◽  
Author(s):  
Karthick Raja Muthu Raja ◽  
Lucie Rihova ◽  
Lenka Zahradova ◽  
Maria Klincova ◽  
Miroslav Penka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Features ◽  
T Regulatory Cells ◽  
Regulatory Cells

Immune Status In Patients with Chronic Lymphocytic Leukemia and Sustained Complete Remission: A Multiparametric Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1389-1389
Author(s):  
Kate E Hodgson ◽  
Gerardo Ferrer ◽  
Carmen Martinez ◽  
Manel Juan ◽  
Tycho Baumann ◽  
...  
Keyword(s):  
T Regulatory Cells ◽  
Immune Status ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
Regulatory Cells ◽  
Cd4 Cells ◽  
Complement Proteins ◽  
Autoimmune Cytopenia ◽  
Normal Controls

Abstract Abstract 1389 Although chronic lymphocytic leukemia (CLL) is considered incurable, a proportion of patients treated with modern therapy achieve complete remission (CR) with minimal residual disease (MRD) negative status, which translates into a better outcome. In addition, survival curves for allogeneic stem cell transplant (alloSCT) appear to plateau, suggesting possible cure. Profound immune disturbances are a major cause of morbidity and mortality in CLL and can be exacerbated by therapy. We studied the immune status of 26 patients with CLL with a sustained (median 8 years, range 2.2 to 17) CR following treatment (4 patients received fludarabine, cyclophosphamide and mitoxantrone [FCM], 6 autologous SCT [autoSCT]) and 16 allogeneic stem cell transplantation [alloSCT]. Lymphocyte subsets were studied using multiparameter flow cytometry and compared to healthy controls. CD8+ T cell response to cytomegalovirus (CMV) was assessed using a pentameric HLA-A2 binding CMV pp65-derived peptide and functionality was confirmed by interferon gamma (IFNγ) ELISPOT. Immunoglobulin subtypes, complement proteins, and β2-microglobulin (B2M) were quantified by standard techniques, interleukin 10 (IL-10) and vascular endothelial growth factor (VEGF) by flow-based cytometric bead array technology, and B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) serum levels by commercial ELISA. Median age at the time of study was 57 years (55 for the alloSCT, 54 for the autoSCT and 63 for the FCM patients). Two alloSCT patients had chronic graft-versus host disease (cGVHD) at sample collection and were receiving immunosuppression. In addition, three patients experienced autoimmune cytopenia after alloSCT, but had responded to therapy at the time of the study. Detectable residual CLL cells (> 10-4) in peripheral blood were found in six patients (3 alloSCT, 3 FCM). The 20 patients in MRD negative CR had a significantly higher absolute B cell count compared to normal controls comprised of both CD19+CD5- cells (154 cells/mm3vs. 76 cells/mm3, p=0.005) and CD19+CD5+ cells (22 cells/mm3vs. 1 cell/mm3, p=0.002). Normal serum levels of immunoglobulin were present in 17 patients whereas 9 had persistent hypogammaglobulinemia (4 were MRD positive, 2 were on immunosuppression for cGVHD and 1 patient had received rituximab). Thus only 2 patients had unexplained hypogammaglobulinemia despite being in MRD negative-CR. T cell abnormalities were also common in these patients. An abnormal CD4:CD8 ratio was present in 9 patients, and CD4+ cells had failed to recover to >400 cells/mm3 in an additional 5 patients. An increase in CD8+ cells (620 cells/mm3vs. 379 cells/mm3 in normal controls) was mostly comprised of cells with a chronically activated phenotype, CD8+DR+ (220 cells/mm3vs. 78 cells/mm3 in normal controls, p=0.062). Furthermore, in CMV+/HLA-A2 patients, an elevated cytotoxic CD3+CD8+CD45RA population was seen (200 cells/mm3vs. 51 cells/mm3, p=0.037). In all cases, cytotoxic T cells expansions secrete IFNγ in response to pp65. As regards T regulatory cells, CD4+CD25+FOXP3+ cells were significantly increased in patients after alloSCT compared to normal controls (4.1% of CD4+ cells vs. 2.05% in normal, p=0.023). In contrast, patients who received either FCM or autoSCT had Treg levels equivalent to our normal samples (2.45% of CD4+ cells), including the three patients who were MRD positive after FCM. B2M was elevated in 7 patients. No differences were found in levels of complement proteins C3 and C4, direct Coombs test, IL-10 and VEGF. Nevertheless, patients showed median BAFF serum levels significantly higher than healthy controls, even when those patients with conditions considered likely to elevate BAFF and APRIL were excluded (cGVHD, autoimmune cytopenia) (p<0.0001). As for APRIL, serum levels were only significantly increased in patients who had received an alloSCT (p<0.001). These results indicate that characteristic immunological defects associated with CLL (i.e, hypogammaglobulinemia, expansion of CD8+CD45RA cells, abnormal levels of cytokines) may persist in patients with CLL in sustained MRD-negative CR independent of therapy. However, T regulatory cells are increased in patients who had received an alloSCT, a finding which may relate to the persistence of an immunologically tolerant environment necessary to permit successful allografting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4+ T regulatory cells

2014 ◽  
Vol 63 (11) ◽  
pp. 1189-1197 ◽  
Author(s):  
Walter Moises Tobias Braga ◽  
Bruna Raphaeli da Silva ◽  
Ana Carolina de Carvalho ◽  
Yumi H. Maekawa ◽  
Adriana Bruscato Bortoluzzo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Regulatory Cells ◽  
Regulatory Cells
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