Telomerase - a tumor antigen in chronic lymphocytic leukemia (CLL) induces spontaneously autologous leukemia specific cytotoxic T lymphocytes

Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I–restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis.

Download Full-text

Molecular, Epigenetic, and Phenotypic Repolarization of T Lymphocytes From Chronic Lymphocytic Leukemia Patients Using 5-Aza-2′-Deoxycytidine

Blood ◽

10.1182/blood.v116.21.4651.4651 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4651-4651

Author(s):

Jason A Dubovsky ◽

John Powers ◽

Yang Gao ◽

Luis F Mariusso ◽

Eduardo M. Sotomayor ◽

...

Keyword(s):

T Cells ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Conflicts Of Interest ◽

Therapeutic Potential ◽

Cell Polarization ◽

Lymphocytic Leukemia ◽

Th2 Cells ◽

Ex Post

Abstract Abstract 4651 The improper polarization of helper and cytotoxic T lymphocytes is a trademark immunosuppressive strategy employed by chronic lymphocytic leukemia (CLL). Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Very recent in-vitro evidence indicates that this plasticity may be phenotypically replicated by using methylation inhibitors which are approved for clinical use in certain types of cancer, however the longevity and therapeutic potential of repolarized cells remains to be elucidated. These results beg the question: can the ineffective polarization of T lymphocytes in the context of CLL be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has focused on repolarizing helper and cytotoxic T lymphocytes using 5-aza-2′-deoxycytidine (5A2) tracking changes in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our studies relied upon intracellular staining, methylation specific PCR, western blot, and phosflow anlaysis. The data indicates that 5A2 treatment can repolarize Th2 cells to effectively secrete interferon gamma, signal via T-bet, and achieve demethylation of critical Th1 specific promoters. We also show that this repolarization can be maintained. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. Finally, we have identified a cytotoxic threshold for 5A2 treatment which is above the concentration necessary to achieve effective and sustained molecular and epigenetic repolarization. All in all our data seeks to define a modality in which improper or ineffective T cell polarization can be altered ex post facto and continued immunotherapeutic intervention may benefit from the naïve polarization of anti-cancer responses. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

CD40 activation does not protect chronic lymphocytic leukemia B cells from apoptosis induced by cytotoxic T lymphocytes

Blood ◽

10.1182/blood.v95.12.3853 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3853-3858 ◽

Cited By ~ 21

Author(s):

Peter Chu ◽

William G. Wierda ◽

Thomas J. Kipps

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Lymphocytic Leukemia ◽

Target Cells ◽

Apoptosis Pathway ◽

Granule Exocytosis ◽

Concanamycin A ◽

Cd40 Activation

Abstract Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I–restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis.

Download Full-text

A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease

Blood ◽

10.1182/blood-2010-12-324210 ◽

2011 ◽

Vol 117 (20) ◽

pp. 5463-5472 ◽

Cited By ~ 120

Author(s):

Davide Bagnara ◽

Matthew S. Kaufman ◽

Carlo Calissano ◽

Sonia Marsilio ◽

Piers E. M. Patten ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Adoptive Transfer ◽

Severe Combined Immunodeficiency ◽

Immune Surveillance ◽

Lymphocytic Leukemia ◽

Unknown Etiology ◽

Lymphoid Tissues ◽

Transfer Model

AbstractChronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γcnull mice under the influence of activated CLL-derived T lymphocytes. By cotransferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4+ T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic factors promoting CLL cell growth, identifying and characterizing potential leukemic stem cells, and permitting preclinical studies of novel therapeutics. Because autologous activated T lymphocytes are 2-edged swords, generating unwanted graph-versus-host and possibly autologous antitumor reactions, the model may also facilitate analyses of T-cell populations involved in immune surveillance relevant to hematopoietic transplantation and tumor cytoxicity.

Download Full-text

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

Russian Clinical Laboratory Diagnostics ◽

10.51620/0869-2084-2021-66-6-345-352 ◽

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.

Download Full-text

T cell chronic lymphocytic leukemia: presence in bone marrow and peripheral blood of cells that suppress erythropoiesis in vitro

Blood ◽

10.1182/blood.v52.1.255.255 ◽

1978 ◽

Vol 52 (1) ◽

pp. 255-260 ◽

Cited By ~ 86

Author(s):

R Hoffman ◽

S Kopel ◽

SD Hsu ◽

N Dainiak ◽

ED Zanjani

Keyword(s):

Bone Marrow ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Peripheral Blood ◽

Lymphocytic Leukemia ◽

Transfusion Therapy ◽

Cell Chronic Lymphocytic Leukemia ◽

Marrow Cells

Abstract The pathogenesis of the anemia associated with malignancy was investigated in a patient with T cell chronic lymphocytic leukemia. The plasma clot culture system was used as a measure in vitro of erythropoiesis. The patient's peripheral blood and marrow T lymphocytes obtained both before and after transfusion therapy suppressed erythroid colony formation by normal human bone marrow cells. Pretreatment of the patient's bone marrow T cells by antithymocyte globulin (ATG) and complement reversed this suppression. In addition, pretreatment of the patient's marrow cells with ATG and complement markedly augmented erythropoiesis in vitro. The expression of erythroid activity caused by the selective destruction of the suppressor T lymphocytes in the patient's bone marrow with ATG and the suppression of normal erythropoiesis by the patient's bone marrow and peripheral blood lymphocytes suggest that interaction between the malignant T cell and the erythropoietin-responsive stem cell is important in production of anemia in this patient.

Download Full-text

CD200 and Chronic Lymphocytic Leukemia: Biological and Clinical Relevance

Frontiers in Oncology ◽

10.3389/fonc.2020.584427 ◽

2020 ◽

Vol 10 ◽

Author(s):

Giovanni D’Arena ◽

Vincenzo De Feo ◽

Giuseppe Pietrantuono ◽

Elisa Seneca ◽

Giovanna Mansueto ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

B Cell ◽

Cell Lymphoma ◽

Prognostic Significance ◽

Cell Types ◽

Lymphocytic Leukemia ◽

Mantle Cell ◽

Type Ia

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin protein superfamily, is broadly expressed on a wide variety of cell types, such as B lymphocytes, a subset of T lymphocytes, dendritic cells, endothelial and neuronal cells. It delivers immunosuppressive signals through its receptor CD200R, which is expressed on monocytes/myeloid cells and T lymphocytes. Moreover, interaction of CD200 with CD200R has also been reported to play a role in the regulation of tumor immunity. Overexpression of CD200 has been reported in chronic lymphocytic leukemia (CLL) and hairy cell leukemia but not in mantle cell lymphoma, thus helping to better discriminate between these different B cell malignancies with different prognosis. In this review, we focus on the role of CD200 expression in the differential diagnosis of mature B-cell neoplasms and on the prognostic significance of CD200 expression in CLL, where conflicting results have been published so far. Of interest, increasing evidences indicate that anti-CD200 treatment might be therapeutically beneficial for treating CD200-expressing malignancies, such as CLL.

Download Full-text

Effect of a thymic factor on T lymphocytes in B cell chronic lymphocytic leukemia: in vitro and in vivo studies

Blood ◽

10.1182/blood.v64.3.667.667 ◽

1984 ◽

Vol 64 (3) ◽

pp. 667-671 ◽

Cited By ~ 7

Author(s):

F Lauria ◽

D Raspadori ◽

S Tura

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

B Cell ◽

Proliferative Response ◽

Lymphocytic Leukemia ◽

Before And After ◽

Cell Chronic Lymphocytic Leukemia

Abstract Abnormalities of T lymphocytes in B cell chronic lymphocytic leukemia (B-CLL) have been extensively documented by several immunologic investigations. Following recent studies pointing to the favorable effect of TP-1, a partially purified extract of calf thymus, on the T cell-mediated immunity of several diseases, including Hodgkin's disease, we have used monoclonal antibodies and the enriched T lymphocytes of 16 untreated B-CLL patients to evaluate the proportion of T cell subsets before and after the administration of TP-1. In addition, the proliferative response to phytohemagglutinin (PHA) and the helper function in a pokeweed mitogen (PWM) system were assessed. In ten cases, the effect of TP-1 was also studied in vitro by evaluating the same parameters before and after incubation of B-CLL T cells with the drug. The study demonstrated that in vivo administration of TP-1 increases significantly (P less than .001) the proportion of the defective helper/inducer T cell population (OKT4-positive cells) in B-CLL, leading to a near normal OKT4/OKT8 ratio. Furthermore, the improved phenotypic profile was accompanied by an increased proliferative response to PHA and, in particular, by a significant increase (P less than .01) of T helper capacity; this increase was, however, insufficient to enable the normalization of the serum immunoglobulin levels. The in vitro incubation of B-CLL T lymphocytes did not succeed in producing significant modifications in distribution and function.

Download Full-text

Lactic dehydrogenase in normal and leukemia lymphocyte subpopulations: evidence for the presence of abnormal T cells and B cells in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v57.2.324.324 ◽

1981 ◽

Vol 57 (2) ◽

pp. 324-327 ◽

Cited By ~ 14

Author(s):

P Rambotti ◽

S Davis

Keyword(s):

T Cells ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

B Lymphocytes ◽

Lactic Dehydrogenase ◽

Isozyme Pattern ◽

Lymphocyte Subpopulations ◽

Lymphocytic Leukemia ◽

Ldh Activity

Abstract Lactic dehydrogenase (LDH) was quantitated and the isozyme pattern studied in lymphocyte subpopulations from normal people and patients with chronic lymphocytic leukemia (CLL). Normal T lymphocytes differed from normal B lymphocytes in having greater total LDH activity (597.2 versus 252.1). Total LDH activity in CLL T cells (347.1) was lower than normal T cells., but not significantly different than normal B cells. Total LDH activity in CLL B cells (124.6) was lower then normal B cells and normal T cells. The isozyme pattern of normal T lymphocytes showed a higher activity in the LDH-1 band (26.7% versus 5.4%) but showed a lower activity in LDH-5 band (4.3% versus 16.3%) compared to normal B cells. Chronic lymphocytic leukemia T cells could be distinguished from CLL B cells by a high LDH-5 band (22.3% versus 7.6%) and from normal T cells by a high LDH-5 band (22.3% versus 4.3%) and a low LDH-1 band (7.3% versus 26.7%). CLL B cells could be distinguished from normal B cells by a low LDH-5 band (7.6% versus 16.3%). Thus, the LDH isozyme pattern distinguishes normal T lymphocytes from normal B lymphocytes, and normal T and B lymphocytes from CLL T and B lymphocytes.

Download Full-text