Alterations Of The Chemokine Microenvironment In Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1619-1619
Author(s):  
TILL M SEILER ◽  
Roland Aydin ◽  
Tobias Herold ◽  
Stefan Holdenrieder ◽  
Michael Hallek ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Advanced Stage ◽  
Healthy Individuals ◽  
T Cell Migration ◽  
Cytokines And Chemokines ◽  
Disease Specific

Abstract Background In chronic lymphocytic leukemia (CLL), proliferation of the leukemic cell clone occurs in the bone marrow and lymphatic tissues rather than peripheral blood. In this microenvironment, CLL cells interact with accessory cells, such as T-cells and CD68+ nurselike cells (NLCs). In addition, cytokines and chemokines secreted by leukemic cells, stromal cells and T-cells are essential in forming the disease-specific microenvironment. However, the exact biological role of cytokines and chemokines needs to be defined. Methods In order to address this issue, we measured serum levels of 20 chemokines and cytokines in a prospective cohort of 159 previously untreated Binet stage A patients (pts) (GCLLSG CLL1 trial), 50 pts with advanced CLL in need of first line treatment (GCLLSG CLL8 trial) and 27 healthy individuals. For the study cohorts, serum samples had been centrally collected at study entry and stored at -80°C. Sera were analyzed on a Luminex-based multiplex platform, allowing simultaneous screening of multiple serum parameters. Results Serum levels of 13 chemokines (EGF, MCP-1, MIP-1alpha, MIP-1beta, sIl2Ralpha, VEGF, MCP-2, MCP-4, SDF-1, 6CKine, CTACK, TRAIL, SCF) differed significantly between healthy controls and CLL patients (p<0.05), indicating that the expression of these cytokines may potentially impact pathways common to CLL and the disease specific microenvironment. In addition, 7 chemokine serum levels were significantly higher in advanced stage CLL compared to patients at primary diagnosis, indicating a pronounced shift of the chemokine homeostasis upon disease progression. (Table) We identified a strong correlation of inflammatory cytokines (TRAIL, TNFalpha; p=0.039), growth factors (EGF, VEGF, TPO, SCF; p<0.001) and chemokines involved in B- and T-cell migration and homing (MIP-1alpha, MIP-1beta, 6CKine, Il-16; p<0.05). These coordinately regulated cytokines may reflect pathways important to the pathobiology of CLL. Hierarchical cluster analyses revealed distinct chemokine expression patterns in healthy individuals, early CLL and advanced stage disease. Finally, sIl2Ralpha has been previously confirmed as an independent prognostic factor in early stage CLL Conclusion Due to the comparison of 27 healthy individuals and 209 CLL pts we were able to demonstrate that the chemokine homeostasis is significantly altered in CLL compared to healthy individuals. Chemokines involved in B- and T-cell migration and homing and recruitment, inflammation and growth factors are coordinately overexpressed, pointing towards pathways crucial to the formation of a disease specific microenvironment. These pathways might serve as potential targets for future therapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

Defective T Cell Migration in Chronic Lymphocytic Leukemia Is Repaired by Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3117-3117
Author(s):  
Alan G. Ramsay ◽  
Lena Svensson ◽  
Nancy Hogg ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Direct Contact ◽  
Immune Surveillance ◽  
Lymphocytic Leukemia ◽  
T Cell Migration

Abstract We have previously demonstrated that multiple gene expression abnormalities are induced in T cells from chronic lymphocytic leukemia (CLL) patients including defects within the actin cytoskeleton signaling pathways that control immune recognition and motility (Gullu et al. JCI, 2005). T cell immune surveillance requires rapid migratory responses and LFA-1 (CD11a/CD18; αLβ2) is a promigratory receptor that engages the cytoskeleton to control migration. We hypothesized that CLL T cells may exhibit dysfunctional migration in response to ICAM-1, the principal ligand for LFA-1. Using time lapse microscopy, we observed significantly reduced chemokine SDF-1 (CXCL12) induced migration on ICAM-1 of CLL CD4 and CD8 T cells compared to age-matched healthy donor T cells. Healthy T cells tracked for 45 min displayed a random course of migration with an average speed of ~ 8 μm/min, whereas CLL T cells were slower ~ 5 μm/min (n=14, ~ 30% reduction, p&lt;0.01). We further postulated that direct contact of CLL tumor cells with healthy T cells would induce this migratory defect. Healthy CD4 or CD8 T cells were cocultured with either allogeneic CLL B cells or allogeneic healthy B cells and subsequently used in migration assays. Co-culture with CLL cells resulted in significantly reduced T cell migration compared with co-culture with healthy B cells (~ 44% reduction in migration, n=6, p&lt;0.01). Evidence that direct contact was required to induce this migratory defect was shown when no effect was observed when cell-cell adhesion was prevented by pretreatment of CLL cells with anti-ICAM-1 blocking antibody prior to primary co-culture with healthy T cells. This cancer-induced migratory defect was repaired when CLL T cells were pretreated with the immunomodulatory drug Lenalidomide (1μM for 1hr). Treatment with this agent enhanced the migratory potential of CLL T cells to a speed comparable to untreated and treated healthy T cells. The finding that lenalidomide can restore rapid migration in patient T cells provides evidence that this agent may increase immune surveillance in CLL patients.

Significantly Shorter Telomeres in T-Cells of ZAP-70+/CD38+ Patients with Chronic Lymphocytic Leukemia (CLL): An Important Role of T-Cells in This Subgroup of CLL?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1120-1120
Author(s):  
Alexander Roeth ◽  
Dirk de Beer ◽  
Holger Nueckel ◽  
Ludger Sellmann ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Memory T Cells ◽  
Lymphocytic Leukemia ◽  
Healthy Individuals ◽  
Cell Numbers

Abstract BACKGROUND: In contrast to other B-cell neoplasias, chronic lymphocytic leukemia (CLL) is not only characterized by a clonal expansion of specific B-cells, but also by an increase in non-leukemic T-cells, most likely involved in sustaining the growth of the leukemic B-cell clone. Based on ZAP-70, CD38 and the IgVH mutation status, two prognostic groups of CLL patients can be identified. Our aim was to characterize the replicative histories of the B- and T-cells in the two groups of CLL patients compared to healthy individuals. PATIENTS and METHODS: Blood samples from 73 patients with CLL (ZAP-70−/CD38−: n = 29, ZAP-70+/CD38+: n = 30, ZAP-70/CD38 discordant: n = 14) were analyzed. The quantity and characteristics of the lymphocyte subsets was assessed by a cell counter and by immunophenotypic analysis. The replicative histories of naive and memory T-cells as well as B-cells was determined by measurements of telomere length in peripheral blood leukocytes of CLL patients and healthy individuals by automated multicolor flow-FISH. RESULTS: As expected, the average telomere length of the clonal B-cells was short. The telomere length was, however, significantly shorter for the ZAP-70+/CD38+ patient samples (2.46 ± 1.08 kb) than for the ZAP-70−/CD38− patient samples (5.06 ± 1.76 kb, p < 6.7 x 10−9). Interestingly, also the naive and memory T-cells from ZAP-70+/CD38+ CLL patients exhibited significantly shorter average telomere lengths (mean ± std: 4.85 ± 1.58 kb; 4.39 ± 1.09 kb) than T-cells from ZAP-70−/CD38− CLL patients (6.64 ± 1.72 kb, p < 2.2 x 10−4; 6.22 ± 1.5 kb, p < 7.4 x 10−6). These results are in line with the observed higher absolute T-cell numbers in the ZAP-70+/CD38+ CLL patients compared to ZAP-70−/CD38− CLL patients. Moreover, the average telomere loss in relation to time from primary diagnosis to sample date was higher for naive T-cells than memory T-cells in ZAP-70+/CD38+ patients (7.8 vs. 5.8 bp/month). When we compared the telomere length to age-related percentiles calculated from over 400 healthy individuals aged 0–102 years practically all telomere length values of the naive and memory T-cells from the ZAP-70+/CD38+ CLL patients fell below the 50th percentile, whereas the values of naive and memory T-cells from the ZAP-70−/CD38− CLL patients were within the normal distribution. CONCLUSIONS: We can confirm significantly shorter telomere length values for the B-cells of the ZAP-70+/CD38+ CLL patients. In addition, we can also demonstrate significantly shorter telomeres in T-cells of ZAP-70+/CD38+ CLL patients, which are below the 50th percentile compared to controls, and a higher telomere loss over time for naive T-cells of ZAP-70+/CD38+ CLL patients. As telomere length shortens approximately 50 to 100 bp per cell division the observed decrease in telomere length of the T-cells in ZAP-70+/CD38+ CLL patients equals to approximately 18 to 36 population doublings. This is by far more than expected by the slightly higher T-cell numbers in the peripheral blood. Our observations imply an extensive expansion of the T-cell compartment in ZAP-70+/CD38+ CLL patients and suggest an important role of T-cells in this subgroup of CLL patients.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

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 Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabel Jiménez ◽  
Bárbara Tazón-Vega ◽  
Pau Abrisqueta ◽  
Juan C. Nieto ◽  
Sabela Bobillo ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Clinical Progression ◽  
Molecular Changes ◽  
Main Driver ◽  
Altered Gene

Abstract Background Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

scholarly journals Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1412-1421 ◽  
Author(s):  
Alan G. Ramsay ◽  
Andrew J. Clear ◽  
Rewas Fatah ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Evasion ◽  
Actin Polymerization ◽  
Rho Gtpase ◽  
Small Gtpases ◽  
Lymphocytic Leukemia ◽  
Functional Screening ◽  
Immunologic Synapse

Abstract Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand–induced impairment of T-cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell–inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer.

Specific features of T- and NK-cellular immunity in chronic lymphocytic leukemia

2021 ◽  
Vol 66 (6) ◽  
pp. 345-352
Author(s):  
Evgeniy Vladimirovich Pochtar ◽  
S. A. Lugovskaya ◽  
E. V. Naumova ◽  
E. A. Dmitrieva ◽  
A. I. Kostin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Lymphocytic Leukemia ◽  
Positive Trend ◽  
Functional Changes ◽  
Activated T Lymphocytes ◽  
T Helpers

Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Billy Michael Chelliah Jebaraj ◽  
Annika Müller ◽  
Rashmi Priyadharshini Dheenadayalan ◽  
Sascha Endres ◽  
Philipp M. Roessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Treatment Benefit ◽  
Btk Inhibitors

Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop by a mutation in cysteine 481 of BTK (C481S), which prevents the irreversible binding of the drugs. In the present study we performed pre-clinical characterization of vecabrutinib, a next generation non-covalent BTK inhibitor, with ITK inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wildtype BTK. In the murine Eµ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, while the naïve populations were increased. Of importance, vecabrutinib treatment significantly reduced frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on activation and proliferation of isolated T-cells. Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.

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