Requirements for control of B‐cell lymphoma by NK cells

Brenner, Christoph; King, Susan; Przewoznik, Margarethe; Wolters, Imke; Adam, Christian; Bornkamm, Georg W.; Busch, Dirk H.; Röcken, Martin; Mocikat, Ralph

doi:10.1002/eji.200939937

Cited by 31 publications

(65 citation statements)

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“…The ability of tumor cells to deliver this activation is probably lost during tumor progression, as suggested in the Burkitt's lymphoma Em-myc mouse model. 48 Based on our data, we propose that the first signal delivered by damaged or transformed target cells relates to exosomes that present activating ligands such as BAG6. A failure of exosome stimulation results in NK cell anergy, further driven by soluble inhibitory factors in the microenvironment (see Figure 7).…”

Section: Discussionmentioning

confidence: 78%

“…This means that activation of NK cells by extracellular ligands "in trans" is possible, which poses the question of how NK cells may retain their specificity against the damaged (and exosomes releasing) target cells. One possible explanation is that NK cells need a second signal as previously discussed 47,48 that is delivered by direct cell-cell contact. The ability of tumor cells to deliver this activation is probably lost during tumor progression, as suggested in the Burkitt's lymphoma Em-myc mouse model.…”

Section: Discussionmentioning

confidence: 99%

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Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Reiners¹,

Topolar²,

Henke³

et al. 2013

Blood

190

171

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Key Points• Exosomal NKp30-ligand BAG6 is crucial for detection of tumor cells by NK cells in vitro and in vivo.• Soluble plasma factors including BAG6 suppress NK cell cytotoxicity and promote evasion of CLL cells from NK cell anti-tumor activity.Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cellreleased soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and downregulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells. (Blood. 2013;121(18):3658-3665) IntroductionChronic lymphocytic leukemia (CLL) patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an anti-tumor immune response. 1 Natural killer (NK) cells, lymphocytes of the innate immune system, are considered to be a major component of the immunosurveillance in leukemia. [2][3][4] However, little is known about the functionality of NK cells and their role in tumor immune escape in CLL.NK cells are tightly regulated by inhibitory or activating "missing self" and "induced self" signals sensed via cell surface receptors. 5 The best examined activating receptors are the Fc receptor CD16, NKG2D, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. Known ligands for NKG2D are the major histocompatibility complex (MHC) class I-related molecules MICA/B and the UL16-binding proteins (ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, and ULBP6) that are induced upon cellular stress on target cells. 6,7 Only a few ligands for the NCRs have been identified to date. [8][9][10][11][12][13][14] Surprisingly, among novel ligands for NKp30 (BAG6 [BAT3], 10 B7-H6 11 ), NKp44 (proliferating cell nuclear antigen 12 ) and NKp46 (vimentin 13,14 ), only B7-H6 is a surface membrane ligand. BAG6, proliferating cell nuclear antigen, and vimentin are proteins without any classical transmembrane domain and are known to exert divergent intracellular functions, including protein sorting and transport, proliferation, and apoptosis. It is still ...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Reiners¹,

Topolar²,

Henke³

et al. 2013

Blood

190

171

View full text Add to dashboard Cite

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“…Interestingly, our data also show that HTR-8 CM (but not ; however, this effect is compromised by direct cellular interactions, as reported in studies regarding tumor-infiltrating NK cells. 33,37,38 Because the IFN-c signaling blockade can improve the EVT expansion in vitro, 39 the suppressed IFN-c production of dNK cells by soluble trophoblastic factors may create a unique microenvironment to facilitate the further invasion of trophoblast cells. However, the in vivo situation is much more difficult to examine due to existing complex molecular networks and cellular interactions.…”

Section: Discussionmentioning

confidence: 99%

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

et al. 2015

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Decidual natural killer (dNK) cells express an array of activation receptors to regulate placental immunity and development during early pregnancy. We investigated the functional character of human dNK cells during the first and second trimester of gestation and the interaction between dNK and trophoblast cells. Although the frequency of CD56CD16 dNK among the total CD45 leukocytes did not change over this period, the expression of the activating receptors, NKp80 and NKG2D, was greatly upregulated. We observed a significantly higher number of extravillous trophoblast cells in proximity to the dNK cells in the first trimester in comparison with the second trimester decidua. NKG2D expression by first trimester dNK cells was decreased when co-cultured with the HTR-8 trophoblast cell line. In the second trimester, functional markers of dNK activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable despite an increase in NKp80 or NKG2D surface expression. Furthermore, the degranulation capacity of dNK cells, as assessed by CD107a, was decreased in the second trimester. We suggest that in the first trimester, trophoblast-dNK interactions generate a population of dNK cells with a suppressed activating phenotype. In the second trimester, the loss of trophoblast-dNK interactions led to the inhibition of dNK cell function, although their activating receptor expression was increased. We speculate that during pregnancy, two mechanisms operate to modulate the dNK cell activation:suppression of activating receptor levels in the first trimester by trophoblasts and disengagement of receptor-ligand coupling in the second trimester.

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“…In parallel, spleen NK cells from tumor-bearing mice did not show defects in cytotoxicity, whereas IFN-␥ production was reduced in response to PMA/Ionomycin, but not to IL-12 stimulation. Recently, Brenner et al [50] reported that in a transgenic mouse model of spontaneously arising lymphoma, effector functions of tumor-infiltrating NK cells became paralyzed during tumor progression.…”

Section: Nk Cells Within the Tumor Microenvironmentmentioning

confidence: 99%

Natural Killer Cells and Solid Tumors

2011

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Natural killer (NK) cells play an important role in the innate immune response against cancer, in particular in the elimination of tumor metastases and small tumors. NK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, such as MHC class I. Thus, we assume that these tumors might be good targets for NK cell-mediated attack. In vitro, NK cells directly kill tumor cells and release soluble factors that affect both innate and adaptive immune responses. To date, in vivo NK cell activation during tumor progression, the influence of the tumor microenvironment on NK cells, and the mechanisms that interfere with their effector function in cancer patients are not completely understood. This review summarizes our current knowledge of NK cells in solid tumors. We will discuss the impact of novel insights into NK cell responses against tumors on the design of NK cell-based therapies.

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Requirements for control of B‐cell lymphoma by NK cells

Cited by 31 publications

References 50 publications

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

Natural Killer Cells and Solid Tumors

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