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

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.

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IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

Cancers ◽

10.3390/cancers13081899 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1899

Author(s):

Selcen Öztürk ◽

Verena Kalter ◽

Philipp M. Roessner ◽

Murat Sunbul ◽

Martina Seiffert

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Mouse Model ◽

Adoptive Transfer ◽

Immune Cell ◽

Immune Escape ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Transfer Model ◽

Leukemia Development

Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.

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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.

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

Blood ◽

10.1182/blood.2021011516 ◽

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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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.

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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.

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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.

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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.

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