scholarly journals Correlation of regulatory T cells in chronic lymphocytic leukemia characterized by high-affinity CD25 expression with serum IL-2 values, IGVH mutational status, Rai stage, and therapeutic lines

2020 ◽  
Vol 67 (3) ◽  
pp. 268-276
Author(s):  
Georgiana Ene ◽  
◽  
Horia Bumbea ◽  
Minodora Onisâi ◽  
Ana-Maria Vlădăreanu ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Lymphocytic Leukemia ◽  
High Affinity ◽  
Cd25 Expression ◽  
Mutational Status ◽  
Igvh Mutational Status

Regulatory T cells in chronic lymphocytic leukemia: implication for immunotherapeutic interventions

Tumor Biology ◽  
2013 ◽  
Vol 34 (4) ◽  
pp. 2031-2039 ◽  
Author(s):  
Farhad Jadidi-Niaragh ◽  
Ghasem Ghalamfarsa ◽  
Mehdi Yousefi ◽  
Mina Hajifaraj Tabrizi ◽  
Fazel Shokri
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Lymphocytic Leukemia

scholarly journals REGULATORY T-CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

2012 ◽  
Vol 4 (1) ◽  
pp. e2012053 ◽  
Author(s):  
Giovanni D'arena ◽  
Giovanni Rossi ◽  
Barbara Vannata ◽  
Silvia Deaglio
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Disease Status ◽  
Lymphocytic Leukemia ◽  
Small Subset ◽  
Systemic Lupus Erythematosis ◽  
Cell Frequency ◽  
Self Tolerance

Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosis, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in either cancer and autoimmune disorders.

scholarly journals Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Cancer ◽  
2010 ◽  
Vol 117 (10) ◽  
pp. 2163-2169 ◽  
Author(s):  
Lukas Weiss ◽  
Thomas Melchardt ◽  
Alexander Egle ◽  
Christoph Grabmer ◽  
Richard Greil ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Initial Treatment ◽  
Early Stage ◽  
Lymphocytic Leukemia

Regulatory T cells in chronic lymphocytic leukemia

2014 ◽  
Vol 39 (2) ◽  
pp. 68
Author(s):  
Tawfik Elkhodary ◽  
Emad Azmy ◽  
Hazem Hakim ◽  
Nadia El Menshawy ◽  
Lamiaa Ebrahim ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Lymphocytic Leukemia

Dexamethasone Induces Apoptosis “Ex Vivo” in Chronic Lymphocytic Leukemia Cells with Either Unmutated IgVH Genes or High ZAP-70 Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2945-2945
Author(s):  
Ana Muntanola ◽  
Marta Crespo ◽  
Eva Gine ◽  
Neus Villamor ◽  
Emili Montserrat ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Viability ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Prognostic Features ◽  
Mutational Status ◽  
Cell Mortality ◽  
Igvh Mutational Status ◽  
Induced Apoptosis

Abstract Patients with chronic lymphocytic leukemia (CLL) and unmutated IgVH genes or high ZAP-70 expression have poorer prognosis than those with mutated IgVH genes or low ZAP-70 levels. This is in part related to the resistance of unmutated and ZAP-70 positive cases to treatment agents that induce apoptosis in a p53-dependent manner. It has been suggested that corticosteroids are active in CLL through p53-independent pathways. The aim of this study was to analyze the “ex vivo” response to dexamethasone in CLL cells according to the IgVH mutational status and ZAP-70 expression. Frozen lymphocytes from 60 patients with CLL were analyzed for ZAP-70 expression and IgVH mutational status (n=44). Cells were cultured and treated using fludarabine (5μgr/ml), mitoxantrone (0.5μgr/ml), FCM (fludarabine 1μgr/ml, maphosphamide 1μgr/ml and mitoxantrone 0.5 μgr/ml), and dexamethasone (5.2 μg/mL). Cell viability and apoptosis were determined by annexinV/PI staining and FACscan analysis at three different time points and conditions (0h and 24h without treatment, and 24h with treatment). The expression of glucocorticoid receptor (GR) isoforms alpha, beta and gamma was analyzed by Quantitative RT-PCR in 20 cases. Dexamethasone-induced apoptosis was significantly higher in patients with unmutated IgVH and/or high ZAP-70 expression (≥20%) than in those with mutated IgVH and/or low ZAP-70 expression (median cell viability 65% vs. 81%, respectively; p<0.001). In contrast, mitoxantrone induced higher cell toxicity in patients with IgVH mutations or low ZAP-70 expression (p=0.009). No differences in cell viability were found according to ZAP-70 expression or IgVH mutational status after “ex vivo” treatment with fludarabine or FCM (p=0.649 and p=0.055, respectively). Expression of different GR isoforms was similar in corticosteroid-responders and non-responders. In conclusion, in this study CLL cells with unmutated IgVH genes or high ZAP-70 expression showed a higher cell mortality after “ex vivo” exposure to dexamethasone than those with mutated IgVH genes or low ZAP-70 expression, with no relationship with the expression of the different GR isoforms. These data give conceptual support to trials aimed at determining the role of dexamethasone in the treatment of patients with CLL and poor prognostic features or resistant to fludarabine. Figure Figure

MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1066-1066
Author(s):  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Dominique Bron ◽  
Benjamin Haibe-Kains ◽  
Pascale Saussoy ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Lymphocytic Leukemia ◽  
Early Therapy ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage

Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P<0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of >312, 129, 80, 36 and 19 months, respectively (HR=17.00, P<0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of >312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P<0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

Clinical-Biological Characterization of Variant B Chronic Lymphocytic Leukemia, Characterized by a Mantle Cell Lymphoma-Like Immunophenotype, t(11;14)(q13;q32) Negative.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1259-1259
Author(s):  
Andrea Ferrario ◽  
Lilla Cro ◽  
Nadia Zucal ◽  
Marta Lionetti ◽  
Francesco Bertoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Mantle Cell Lymphoma ◽  
Statistical Difference ◽  
Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Mutational Status ◽  
Mantle Cell ◽  
Igvh Mutational Status

Abstract Abstract 1259 Poster Board I-282 We describe the clinical-biological features of 63 cases of variant B chronic lymphocytic leukemia (v-B-CLL), characterized by a mantle cell lymphoma-like immunophenotype, atypical cytomorphology in absence of t(11;14)(q13;q32) in FISH analysis. A historical series of 130 B-CLL was used as comparison. The v-B-CLL were significantly different from the B-CLL in terms of the following clinico-hematological variables: age <70 yrs (p <.001), lymphocytosis <20 × 109/ (p <.001), lymphocyte doubling time < 12 months (p = .02), high serum β2-microglobulin levels (p <.001), and splenomegaly (p = .002). Considering immunophenotipic features, CD38 and CD49d expression were significantly more expressed in v-B-CLL than B-CLL (p <.001); whereas, no statistical difference was observed for ZAP-70 reactivity. Considering the IgVH mutation status, there were more patients mutated in the v-B-CLL group than in the B-CLL group (p = .001). Other significant differences were found about the frequency of the recurrent chromosome alterations, evaluated by means of FISH analysis: trisomy 12 was more frequent in v-B-CLL ( p<.001), while del13q14, considered as a single alteration, was more frequent in B-CLL (p=.008). Gene expression profiling of a panel of 9 v-B-CLL compared with 60 B-CLL samples indicated that the variant group is characterized by a specific molecular pattern of gene expression. In particular we observed the upregulation of tumor protein D52 (TPD52), and that of 6 genes (AFF1, GMPS, PICALM, JUN, REL, RAC2) known to be protooncogenes. Furthermore, we found that upregulated genes with apoptosis related functions (IL-7, HSP90B1, NOTCH2, BECN1, ANXA4, MCL1) are all negative regulators of apoptosis. Microarray analysis revealed that various genes (TRIM38, EEF1D, CASP1, MALT1, RHOH0) involved in the I-kB kinase/NF-kB cascade of the canonical NF-kB signaling pathway, are furtherly upregulated in v-B-CLL. Furthermore, among the genes found differentially expressed in SAM analysis, we observed also the upregulation of CD1c (according to the surface expression of this antigen), OSBPL3 and ITGA4. After a median follow-up of 55 months (range 4-196) and 60 months (range 6-180), 25/42 (59%) v-CLL and 55/93 (59 %) CLL pts were treated. TTT was significant different between 2 groups when the IgVH mutational status was considered (p= .006). Median OS of v-CLL subset was 112 months vs 171 months of CLL subset. When the IgVH mutational status was considered, mutated cases showed a worse OS even if a statistical difference was not observed (p= 0.062). In conclusion, our study identifies, on the basis of a defined CFM-FISH diagnostic approach, a variant form of B-CLL that shows peculiar biological and clinical features that should be considered in the future clinical and prognostic studies. The inclusion of this form in B-CLL study could alter the interpretation of results, especially related to biological markers. Disclosures No relevant conflicts of interest to declare.

Marrow-Infiltrating T Cells In Patients with Chronic Lymphocytic Leukemia Display Markers of Functional Impairment and Express PD-1

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2417-2417
Author(s):  
Ursula Hainz ◽  
Quinlan L. Sievers ◽  
Kristen Stevenson ◽  
Natalie R. Goldstein ◽  
David Dorfman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Immunohistochemical Staining ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Effector Memory ◽  
Cell Phenotype

Abstract Abstract 2417 Marrow is a major site of disease development and progression for chronic lymphocytic leukemia (CLL), as well as a priming site for antigen-specific T cells and a reservoir for memory T cells. To determine the extent to which T cells in the marrow microenvironment have an altered phenotype and function in CLL, we analyzed the immunophenotypic characteristics of marrow-infiltrating T cells of 18 CLL patients compared to 11 normal donors. Chemotherapy-naïve CLL patients (n=7) possessed comparable quantities of marrow T cells compared to normal donors (median CD8+ T cells/μl = CLL 904 vs normal 1247; median CD4+ T cells/μl = CLL 1975 vs normal 1110). However, we identified several aberrant characteristics among T cells infiltrating the marrow of CLL patients. First, the ratio of CD8+ to regulatory T cells (CD4+CD25+FOXP3+) was depressed (median ratio CLL 14 vs normal 41), indicating more regulatory T cells per effector T cells in CLL. Second, compared to normal marrow T cells, CLL marrow contained proportionally fewer functional effector CD8+ T cells (CD27+CD28+)(median normal 57%, CLL 48%) and more immunosenescent cells (CD27-CD28-)(median normal 21%, CLL 30%). Third, the T cell differentiation state of CLL CD8+ T cells was skewed to favor a phenotype of increased terminal differentiation (CD45RA+CCR7-)(median CLL 55% vs normal 40%), and decreased naïve (CD45RA+CCR7+) cells (median CLL 21% vs normal 31%) compared to normal donors. These differences were further accentuated in CLL samples collected within 4 months from treatment with conventional chemotherapy (n=11). Finally, by immunohistochemical staining of CLL marrow biopsies, we observed marrow-infiltrating lymphocytes to express PD-1 (mean of infiltrating T cells, untreated CLL 12%, treated CLL 35%, present even >6 months after therapy), a marker associated both with immuno-activation and inhibition. While the majority of PD-1+ CD8 T cells of normal donors (n=5) and treated CLL patients (n=4) were differentiated towards effector memory (CD45RA-CCR7-) cells (median normal 46% vs untreated CLL 16%, p=0.07; treated CLL 61%), the PD-1+ T cells from untreated CLL patients (n=5) were terminally differentiated (CD45RA+CCR7+)(median normal 23% vs untreated CLL 65%, p=0.04; treated CLL 24%). These results indicate an exhausted rather than an activated T cell phenotype in untreated patients. Paired immunophenotypic analysis on blood and marrow from the same individuals (n=9) demonstrated an increased percentage and intensity of PD-1 expression on T cells from marrow compared to blood (percentage CD8+ T cells BM vs blood p = 0.05). Interestingly, PD-1 was also detected on CLL cells (n=16) but not normal B cells (median normal 0%, vs CLL 17%, p = 0.004). The ligand for PD-1, PD-L1, was detected in the marrow vasculature by immunohistochemical staining of biopsies, suggesting that the marrow microenvironment plays a role in the induction of PD-1 associated immunosuppression. Ligation of blood PD-L1 on CLL-T cells led to a 2-fold decrease in activation (measured as CD69 expression) of CD3/CD28 stimulated patient T cells. In summary, we identify several phenotypic and functional alterations within marrow-infiltrating T cells of CLL patients. We speculate these together may contribute to impaired priming of host immunity against the tumor. The PD-1 pathway appears to be activated in CLL, especially in the setting of chemotherapeutic treatment. Since anti-PD1 antibodies are now clinically available, it may be possible to target this pathway to improve anti-tumor responses. Disclosures: No relevant conflicts of interest to declare.

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