Morphological variants of leukemic cells in B chronic lymphocytic leukemia are associated with different T cell and NK cell abnormalities

Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.

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A case of chronic lymphocytic leukemia with properties characteristic of natural killer cells

Blood ◽

10.1182/blood.v61.5.940.940 ◽

1983 ◽

Vol 61 (5) ◽

pp. 940-948 ◽

Cited By ~ 39

Author(s):

K Itoh ◽

K Tsuchikawa ◽

T Awataguchi ◽

K Shiiba ◽

K Kumagai

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Nk Cells ◽

Natural Killer ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Leukemia Cells ◽

Surface Markers ◽

T Antigens ◽

Homogeneous Population

Abstract A case of chronic lymphocytic leukemia that consisted of a homogeneous population of cells that had properties similar to those described for natural killer (NK) cells is presented. These leukemic cells had a morphology of large granular lymphocytes (LGL) and receptors for sheep erythrocytes (ER) and for the Fc portion of IgG (Fc gamma-R). They expressed pan-T antigens OKT3 and Leu-4, but neither helper/inducer T- cell differentiation antigens OKT4 and Leu-3a nor cytotoxic/suppressor T-antigens OKT8 and Leu-2a. HNK 1 antigen, which can be expressed on human NK cells, could be detected on almost all leukemic cells (LGL), whereas a myeloid differentiation antigen, OKM1, which can be expressed on macrophages, granulocytes, and NK cells, was not detected. Thus, it was concluded that the leukemia cells had a characteristic profile of the surface markers: ER+, Fc gamma-R+, HNK-1+, OKT3+, Leu-4+, OKT4-, OKT8-, Leu-3a, Leu-2a, and OKM1-. Although freshly isolated leukemic cells showed no cytotoxicity on NK targets, after incubation at 37 degrees C, the cells did show a potent cytotoxicity on targets of erythroleukemic cell, T cell, and monocyte (but not B cell) origins. When the cells were incubated at 37 degrees C, interferon (IFN gamma) was spontaneously produced in the culture fluids. Treatment with anti- HNK-1 and complement completely abrogated expression of NK activity and interferon production of the patient's lymphocytes in culture. These characteristic features of surface markers and functions strongly suggest the possibility that the leukemia cells of this case are of NK cell origin. The relationship between this case and chronic lymphocytic leukemia of T-cell origin is discussed.

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Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.2519.2519 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2519-2519 ◽

Cited By ~ 1

Author(s):

Chia-Huey Lin ◽

Thomas Kerkau ◽

Christine Guntermann ◽

Martin Trischler ◽

Niklas Beyersdorf ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Activation Markers ◽

Cell Chronic Lymphocytic Leukemia

Abstract B cell chronic lymphocytic leukemia (B-CLL) is characterised by an accumulation of malignant B cells, and impaired humoral and cellular immune responses. Evasion strategies of leukemic cells appear to involve down-regulation of co-stimulatory molecules as well as increased resistance to apoptosis. Here we provide data supporting a novel concept to treat B-CLL with a humanized, superagonistic monoclonal antibody specific for CD28 (TGN1412). Superagonistic anti-CD28 antibodies have been shown to activate human T cells in vitro without requirement for engagement of the T cell antigen receptor (Luhder et al., J. Exp. Med. 2003. 197(8):955–66). Indicative of their activation, TGN1412-triggered T cells from healthy donors upregulate, among other activation markers, CD40L, that has been reported to promote anti-leukemic effects when ectopically expressed on B-CLL cells (Wierda et al., Blood. 2000. 96 (9): 2917–2924). In this report, the responses of PBMCs from B-CLL patients to soluble TGN1412 were examined. We show that in a dose-dependent fashion, polyclonal T cell activation was induced by TGN1412 including proliferation, cytokine production and induction of activation markers such as CD25, CD71, CD134 (Ox40), CTLA-4 (CD152) and CD154 (CD40L). Significantly, modulation of malignant B-CLL cells was also observed. MHC class II molecules (HLA-DR), CD95 and the co-stimulatory molecules CD80 and CD86, but not the proliferation marker Ki-67, were strongly up-regulated upon TGN1412 stimulation. These data suggested that improved antigen-presenting functions of B-CLL cells were induced by TGN1412. Accordingly, preliminary data indicate that B-CLL cells isolated from TGN1412 stimulated cultures induced enhanced proliferation of both allogeneic and autologous T cells, and importantly, TGN1412 activated T cells exhibited enhanced CTL-activity against B-CLL cells. In conclusion, our data suggest that TGN1412 induces polyclonal T cell expansion and activation as well as increased APC function of B-CLL cells. They imply that TGN1412 may have future therapeutic benefit for B-CLL patients.

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A case of chronic lymphocytic leukemia with properties characteristic of natural killer cells

Blood ◽

10.1182/blood.v61.5.940.bloodjournal615940 ◽

1983 ◽

Vol 61 (5) ◽

pp. 940-948

Author(s):

K Itoh ◽

K Tsuchikawa ◽

T Awataguchi ◽

K Shiiba ◽

K Kumagai

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Nk Cells ◽

Natural Killer ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Leukemia Cells ◽

Surface Markers ◽

T Antigens ◽

Homogeneous Population

A case of chronic lymphocytic leukemia that consisted of a homogeneous population of cells that had properties similar to those described for natural killer (NK) cells is presented. These leukemic cells had a morphology of large granular lymphocytes (LGL) and receptors for sheep erythrocytes (ER) and for the Fc portion of IgG (Fc gamma-R). They expressed pan-T antigens OKT3 and Leu-4, but neither helper/inducer T- cell differentiation antigens OKT4 and Leu-3a nor cytotoxic/suppressor T-antigens OKT8 and Leu-2a. HNK 1 antigen, which can be expressed on human NK cells, could be detected on almost all leukemic cells (LGL), whereas a myeloid differentiation antigen, OKM1, which can be expressed on macrophages, granulocytes, and NK cells, was not detected. Thus, it was concluded that the leukemia cells had a characteristic profile of the surface markers: ER+, Fc gamma-R+, HNK-1+, OKT3+, Leu-4+, OKT4-, OKT8-, Leu-3a, Leu-2a, and OKM1-. Although freshly isolated leukemic cells showed no cytotoxicity on NK targets, after incubation at 37 degrees C, the cells did show a potent cytotoxicity on targets of erythroleukemic cell, T cell, and monocyte (but not B cell) origins. When the cells were incubated at 37 degrees C, interferon (IFN gamma) was spontaneously produced in the culture fluids. Treatment with anti- HNK-1 and complement completely abrogated expression of NK activity and interferon production of the patient's lymphocytes in culture. These characteristic features of surface markers and functions strongly suggest the possibility that the leukemia cells of this case are of NK cell origin. The relationship between this case and chronic lymphocytic leukemia of T-cell origin is discussed.

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Poorly expressed CD2 antigen on the leukemic cells of adult T-cell leukemia and chronic lymphocytic leukemia of T-cell lineage

Leukemia Research ◽

10.1016/0145-2126(89)90037-4 ◽

1989 ◽

Vol 13 (1) ◽

pp. 93-99 ◽

Cited By ~ 4

Author(s):

Kazuo Tamura ◽

Kimitaka Sagawa ◽

Hiroyuki Satoh ◽

Junichiro Torigoe ◽

Nobuhiro Kimura ◽

...

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Cell Lineage ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

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Dual B and T markers in acute and chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v55.1.16.bloodjournal55116 ◽

1980 ◽

Vol 55 (1) ◽

pp. 16-20

Author(s):

KA Foon ◽

RJ Billing ◽

PI Terasaki

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

B Lymphocyte ◽

Surface Membrane ◽

Lymphocytic Leukemia ◽

Rosette Formation ◽

Leukemic Cells ◽

Cell Markers ◽

Membrane Immunoglobulin

Leukemic cells from 20 patients with chronic lymphocytic leukemia (CLL) and 60 patients with acute lymphocytic leukemia (ALL) were studied for T- and B-lymphocyte cell surface membrane markers. B-cell markers included surface membrane immunoglobulin, erythrocyte-antibody complement rosette formation, and B-cell (a-like or HLA-DR) antigens detected by a B-cell antiserum. T-cell markers included spontaneous sheep red blood cell rosette formation and a cytotoxic reaction to a specific T-cell antiserum. Seven patients with CLL and two with ALL had dual B and T markers. We propose that dual B- and T-cell markers are more common in CLL and ALL patients than previously reported. With newer and more sensitive tests for identification of B and T cells, this observation may be recognized more frequently.

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Dual B and T markers in acute and chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v55.1.16.16 ◽

1980 ◽

Vol 55 (1) ◽

pp. 16-20 ◽

Cited By ~ 44

Author(s):

KA Foon ◽

RJ Billing ◽

PI Terasaki

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

B Lymphocyte ◽

Surface Membrane ◽

Lymphocytic Leukemia ◽

Rosette Formation ◽

Leukemic Cells ◽

Cell Markers ◽

Membrane Immunoglobulin

Abstract Leukemic cells from 20 patients with chronic lymphocytic leukemia (CLL) and 60 patients with acute lymphocytic leukemia (ALL) were studied for T- and B-lymphocyte cell surface membrane markers. B-cell markers included surface membrane immunoglobulin, erythrocyte-antibody complement rosette formation, and B-cell (a-like or HLA-DR) antigens detected by a B-cell antiserum. T-cell markers included spontaneous sheep red blood cell rosette formation and a cytotoxic reaction to a specific T-cell antiserum. Seven patients with CLL and two with ALL had dual B and T markers. We propose that dual B- and T-cell markers are more common in CLL and ALL patients than previously reported. With newer and more sensitive tests for identification of B and T cells, this observation may be recognized more frequently.

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Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

International Journal of Molecular Sciences ◽

10.3390/ijms21051825 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1825 ◽

Cited By ~ 8

Author(s):

Francesca Arruga ◽

Benjamin Baffour Gyau ◽

Andrea Iannello ◽

Nicoletta Vitale ◽

Tiziana Vaisitti ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Immune Responses ◽

T Lymphocyte ◽

Molecular Mechanisms ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Adaptive Immune

Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.

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Expression of interleukin-2 receptor on T cell chronic lymphocytic leukemia cells and their response to interleukin-2

Blood ◽

10.1182/blood.v67.2.316.bloodjournal672316 ◽

1986 ◽

Vol 67 (2) ◽

pp. 316-321

Author(s):

M Tsudo ◽

T Uchiyama ◽

H Umadome ◽

Y Wano ◽

T Hori ◽

...

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Activated T Cells ◽

Cell Chronic Lymphocytic Leukemia

We analyzed peripheral blood leukemic cells from six patients with T cell chronic lymphocytic leukemia (T-CLL) with monoclonal antibodies including the anti-Tac antibody, which recognizes the receptor for interleukin 2 (IL 2). The patients were divided into two groups according to the reactivity of the monoclonal antibodies. Leukemic cells from three patients with T-CLL reacted with OKT3 and T4 but not T8, whereas those from the remaining three patients reacted with OKT3 and T8 but not T4. IL 2 receptor, which is expressed on activated T cells but not on resting T cells, was preferentially expressed on T4+ T- CLL cells. The IL 2 receptor on T4+ T-CLL cells was indistinguishable from that on normal activated T cells with respect to molecular weight and downregulation by the anti-Tac antibody. Moreover, fresh T4+ T-CLL cells, but not T8+ T-CLL cells, proliferated in response to exogenous IL 2 without prior activation, and this proliferation was inhibited by the anti-Tac antibody. These results suggest that malignant growth of T4+ T-CLL cells can be regulated by IL 2 not only in vitro but also in vivo.

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Establishment of an interleukin 2-dependent human T cell line from a patient with T cell chronic lymphocytic leukemia who is not infected with human T cell leukemia/lymphoma virus

Blood ◽

10.1182/blood.v70.4.1069.bloodjournal7041069 ◽

1987 ◽

Vol 70 (4) ◽

pp. 1069-1072 ◽

Cited By ~ 4

Author(s):

T Hori ◽

T Uchiyama ◽

M Tsudo ◽

H Umadome ◽

H Ohno ◽

...

Keyword(s):

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Cell Line ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Cell Leukemia ◽

Human T Cell ◽

Human T Cell Line ◽

Cell Chronic Lymphocytic Leukemia

We established an interleukin 2 (IL-2)-dependent human T cell line, Kit 225, from a patient with T cell chronic lymphocytic leukemia (T-CLL) with OKT3+, -T4+, -T8- phenotype. Southern blot analysis showed that Kit 225 is not infected with human T cell leukemia/lymphoma virus (HTLV) type I or II, and is probably derived from the major clone in the fresh leukemic cells. Kit 225 cells express a large amount of IL 2 receptors constitutively and their growth is absolutely dependent on IL 2. No other stimuli, such as lectins or antigens, are required for maintaining the responsiveness to IL 2. As abnormal IL 2 receptor expression was also seen originally in the fresh leukemic cells, the establishment of this cell line with IL 2 suggests that IL 2-mediated T cell proliferation is involved in the leukemogenesis of some cases of HTLV-negative T-CLL.

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