Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding

Huergo-Zapico, Leticia; González-Rodríguez, Ana Pilar; Contesti, Juan; González, Esther; López‐Soto, Alejandro; Fernández-Guizán, Azahara; Acebes-Huerta, Andrea; Toyos, Juan R. de los; López‐Larrea, Carlos; Groh, Veronika; Spies, Thomas A.; González, Segundo

doi:10.1007/s00262-011-1195-z

Cited by 42 publications

(32 citation statements)

References 28 publications

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“…42 Interestingly, neither any of these studies nor an independent report 15 demonstrate diminished NKG2D surface expression on NK cells from CLL patients, although an association of MICA levels with the down-modulation of NKG2D surface expression on CD8 T cells was recently described for CLL. 43 It is still controversially being discussed whether the immune escape through soluble NKG2D ligands is due to a passive blocking of the receptor, or rather to an active downregulation of NKG2D on effector cells. 6,44 Here, we report that CLL plasma did not cause a significant down-regulation of NKG2D on healthy donor NK cells, despite high expression of soluble NKG2D ligands (Figure 4B-D).…”

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

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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: 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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“…ERp5 reduces a deeply buried disulfide bond in the membrane-proximal MICA α3 domain, thereby likely generating a conformational change that enables proteolytic cleavage of MICA. This physical relationship is reflected by positive correlations between ERp5 and MICA/B on the surface of leukemic cells and soluble ligands in multiple myeloma and CLL (51, 52). Recruitment of MICA into cholesterol-enriched membrane lipid microdomains by palmitoylation of cysteine residues in its cytoplasmic tail may promote shedding although there is no confirmatory evidence in cancer cells (53).…”

Section: Regulation Of Nkg2d Ligand Sheddingmentioning

confidence: 99%

Immunobiology and Conflicting Roles of the Human NKG2D Lymphocyte Receptor and Its Ligands in Cancer

El‐Gazzar

Groh

Spies

2013

The Journal of Immunology

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Cancers adopt diverse strategies to safeguard their survival, which often involve blinding or incapacitating the immune response, thereby gaining battleground advantage against the host. In immune responses against cancer, an important stimulatory lymphocyte receptor is NKG2D because the tumor-associated expression of its ligands promotes destruction of malignant cells. However, with advanced human cancers profound changes unfold, wherein NKG2D and its ligands are targeted or exploited for immune evasion and suppression. This negative imprinting on the immune system may be accompanied by another functional state wherein cancer cells co-opt expression of NKG2D to complement the presence of its ligands for self-stimulation of tumor growth and presumably malignant progression. This review emphasizes these conflicting functional dynamics at the immunity – cancer biology interface in humans, within an overview of the immunobiology of NKG2D and mechanisms underlying the regulation of its ligands in cancer, with reference to instructive clinical observations and translational approaches.

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“…While the majority of leukemia patients are positive for at least one type of NKG2DL, the combination of several distinct ligands on the cell surface is highly restricted 26 . The absence of integral NKG2DL correlates with a higher degree of release of these ligands in the soluble form, an occurrence detected mainly for MICA, MICB, and ULBP2, all of which have been found in numerous types of hematological malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL) 26 - 29 …”

Section: Soluble Nkg2dl In Tumor Cellsmentioning

confidence: 99%

“…Protein disulfide isomerase family A, member 6 (PDIA6, best known as ERp5) is a member of the family of thiol isomerases that assists in the folding of nascent proteins 29 . Heat shock 70kDa protein 5 (HSPA5, best known as GRP78) is another endoplasmic reticulum protein which co-regulates protein folding mediated by the protein disulfide isomerase family, including ERp5 protein 68 .…”

Section: Mechanisms Involved In the Secretion Of Snkg2dlmentioning

confidence: 99%

Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

2014

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Natural Killer Group 2 member D (NKG2D) activating receptor, present on the surface of various immune cells, plays an important role in activating the anticancer immune response by their interaction with stress-inducible NKG2D ligands (NKG2DL) on transformed cells. However, cancer cells have developed numerous mechanisms to evade the immune system via the downregulation of NKG2DL from the cell surface, including the release of NKG2DL from the cell surface in a soluble form. Here, we review the mechanisms involved in the production of soluble NKG2DL (sNKG2DL) and the potential therapeutic strategies aiming to block the release of these immunosuppressive ligands. Therapeutically enabling the NKG2D-NKG2DL interaction would promote immunorecognition of malignant cells, thus abrogating disease progression.

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Expression of ERp5 and GRP78 on the membrane of chronic lymphocytic leukemia cells: association with soluble MICA shedding

Cited by 42 publications

References 28 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

Immunobiology and Conflicting Roles of the Human NKG2D Lymphocyte Receptor and Its Ligands in Cancer

Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

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