Enhanced formation and survival of CD4+CD25hiFoxp3+T-cells in chronic lymphocytic leukemia

Jak, Margot; Mous, Rogier; Remmerswaal, Ester B. M.; Spijker, René; Jaspers, Annelieke; Yagüe, Adriana; Eldering, Eric; Lier, R. A. W. Van; Oers, Marinus H. J. van

doi:10.1080/10428190902803677

Cited by 101 publications

(89 citation statements)

References 43 publications

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“…Indeed higher than normal numbers of T regulatory cells have been found in CLL patients. [36][37][38][39] We show here that T regulatory cells (CD4 We further demonstrated that TGFb was the major cytokine involved in suppression of T-cell proliferation ( Figure 5B) and, in agreement with functional studies, NLC showed higher levels of TGFb mRNA expression than did normal monocytes. However, since simultaneous addition of antibodies against TGFb and IL-10, and IDO inhibitors resulted in greater and more significant effects when CLL-monocytes were co-cultured with T cells, it is likely that multiple factors cooperate in immunosuppression.…”

Section: Discussionsupporting

confidence: 68%

Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nderived from co-culture of monocytes and autologous leukemic cells are characterized by a gene expression profile typical of cells with dysregulated immunocompetence which could be relevant in the context of the acquired immunodeficiency commonly found in CLL patients. 12Whether NLC represent CLL-specific tumor-associated macrophages, as recently suggested, 13 is still debated. We have recently reported that hepatocyte growth factor (HGF), together with CXCL12, is produced at high levels by stromal cells and is capable of prolonging the survival of CLL cells which are positive for the HGF receptor, c-MET.14 HGF is a multifunctional cytokine that induces multiple biological responses in target cells, including adhesion, motility, growth, survival and morphogenesis by activating its tyrosine kinase receptor, c-MET. 15,16 In normal individuals, HGF is constitutively produced by fibroblast-like stromal cells in lymphoid tissue and by follicular dendritic cells within the germinal center microenvironment. 15,17,18 NLC are present in the lymph nodes of CLL patients, where they are interspersed with stromal, dendritic and T cells to form proliferation centers. 19 The intriguing finding that HGF levels are higher in sera from CLL patients than from normal controls, 20 together with a still undefined pattern of effects induced by HGF on myelomonocytic cells, prompted us to determine c-MET expression on NLC and on monocytes-macrophages as well as investigate potential downstream events caused by the interaction between HGF and c-MET. MethodsThis study was approved by the review board of the IRCCS AOU San Martino -IST, Genoa, Italy. Full details are provided in the Online Supplementary Methods file. Cell preparationHeparinized blood or bone marrow samples were taken from CLL patients untreated for at least 3 months. The patients' characteristics are summarized in Online Supplementary Table S1. NLC were derived and characterized as described below and in the Online Supplementary Methods. CD14 + monocytes were purified from patients or healthy donors by magnetic beads. The human monocytic cell line THP-1 was utilized in selected experiments. Fluorescence microscopy and flow cytometryNLC or fresh monocytes from CLL or normal donors were challenged with antibodies against c-MET, indoleamine 2,3-dioxygenase (IDO), vimentin, CD68, interleukin (IL)-10, CD14, CXCR4, CD163 and pSTAT3 TYR705 and analyzed by immunofluorescence or flow cytometry. The quantification of pSTAT3 immunopositive cells area is described in detail in the Online Supplementary Methods. Analysis of STAT3 and pSTAT3 activation by western blottingWestern blotting was used to evaluate STAT3, pSTAT3 and bactin in monocytes from normal or CLL donors and in NLC with or without HGF treatment. Immunohistochemistry and immunofluorescence analysis of lymph node and bone marrow biopsiesTissue sections were probed with anti-human c-MET, -IDO, -vimentin, -CD68, and -CD163. 3,3'-Diaminobenzidine (DAB) substrate chromogen...

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Section: Discussionsupporting

confidence: 68%

Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

et al. 2014

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“…15,28 This relative NK-cell anergy could be due to the ability of CLL cells and their microenvironment to produce cytokines, such as IL-10, which suppress the proliferation of antigen-specific Th1 cells and downregulate co-stimulatory molecules on antigen-presenting cells. [29][30][31] Importantly, NK-cell function was perfectly recovered following activation. This included the ability to produce large amounts of IFN-g after IL-12 and IL-18 activation, and effective cytolysis against major histocompatibility complex % NK ADCC class-I-defective K562 target cells after IL-2 activation.…”

Section: Discussionmentioning

confidence: 90%

Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies

et al. 2010

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Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FccRIIIA) is well preserved in CD16 þ CD56 dim cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FccRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FccR engagement in CLL patients.

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“…As a result, CD70 expression is tightly regulated, and it is only transiently expressed on activated T and B cells, as well as on subsets of professional antigen-presenting dendritic cells (DC) and natural killer (NK) cells (11). In contrast to the very limited expression of CD70 in a normal healthy individual, constitutive expression of CD70 has been documented in cancer (17)(18)(19) and chronic viral diseases (14).…”

Section: Cells This Conversion Of Naive T Cells To Induced (I)tregs mentioning

confidence: 99%

CD27 Signaling Increases the Frequency of Regulatory T Cells and Promotes Tumor Growth

et al. 2012

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Signaling of the TNF receptor superfamily member CD27 activates costimulatory pathways to elicit T-and B-cell responses. CD27 signaling is regulated by the expression of its ligand CD70 on subsets of dendritic cells and lymphocytes. Here, we analyzed the role of the CD27-CD70 interaction in the immunologic control of solid tumors in Cd27-deficient mice. In tumor-bearing wild-type mice, the CD27-CD70 interaction increased the frequency of regulatory T cells (Tregs), reduced tumor-specific T-cell responses, increased angiogenesis, and promoted tumor growth. CD27 signaling reduced apoptosis of Tregs in vivo and induced CD4 þ effector T cells (Teffs) to produce interleukin-2, a key survival factor for Tregs. Consequently, the frequency of Tregs and growth of solid tumors were reduced in Cd27-deficient mice or in wild-type mice treated with monoclonal antibody to block CD27 signaling. Our findings, therefore, provide a novel mechanism by which the adaptive immune system enhances tumor growth and may offer an attractive strategy to treat solid tumors. Cancer Res; 72 (14); 3664-76. Ó2012 AACR.

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Enhanced formation and survival of CD4⁺CD25^hiFoxp3⁺T-cells in chronic lymphocytic leukemia

Cited by 101 publications

References 43 publications

Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages

Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies

CD27 Signaling Increases the Frequency of Regulatory T Cells and Promotes Tumor Growth

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