Mimicking an Induced Self Phenotype by Coating Lymphomas with the NKp30 Ligand B7-H6 Promotes NK Cell Cytotoxicity

Kellner, Christian; Maurer, Tina; Hallack, Daniela; Repp, Roland; Winkel, Jan G. J. van de; Parren, Paul W.H.I.; Valerius, Thomas; Humpe, Andreas; Gramatzki, Martin; Peipp, Matthias

doi:10.4049/jimmunol.1201321

Cited by 48 publications

(60 citation statements)

References 46 publications

(76 reference statements)

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“…Previous in vitro studies have also suggested that B7-H6 may be useful for treatment to target tumor cells expressing B7-H6 (3,19,27). Incubation of lymphoma cells with a fusion protein containing B7-H6 and 7D8, an antibody that recognizes CD20, enhanced NK cell activation and cytotoxicity in vitro (28). In the present study, the analysis of 305 tissue samples from patients with breast cancer did not suggest that B7-H6 has an antitumor function.…”

Section: Percentage Of Patients -------------------------------------mentioning

confidence: 61%

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

Sun

Hong

et al. 2017

Oncology Letters

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Abstract. B7 homolog 6 (B7-H6), a member of the B7 family, is as a cell-surface ligand for natural cytotoxicity triggering receptor 3, which is expressed on natural killer cells. It has previously been reported that B7-H6 is undetectable in normal human tissues but is expressed on tumor cells. However, there are few studies focusing on the clinical significance of B7-H6 expression in human carcinoma, with the exception of three studies on ovarian, lung and gastric cancer. The present study investigated the expression of B7-H6 protein in pathologic tissue samples from 305 patients with breast cancer using immunohistochemistry. A high B7-H6 expression level was identified in tissues from 32.13% of patients with breast cancer. These patients were revealed to also exhibit a high expression level of human epidermal growth factor receptor 2, a shorter survival time and a higher rate of lymph node metastasis. Furthermore, the expression level of B7-H6 was not associated with patient age, breast cancer subtype, tumor size, tumor location or estrogen receptor expression. The results of the present study revealed that higher B7-H6 expression level in breast cancer tissues was positively associated with tumor progression. This indicates that B7-H6 is associated with the progression and immunoevasion of human breast cancer; however, the molecular mechanisms underlying this potential effect require further investigation. IntroductionB7 homolog 6 (B7-H6), a novel member of the B7 family, was identified on tumor cell surfaces in 2009 (1). B7-H6 has sequence homology with other B7 molecules and similar to other members of the B7 family, B7-H6 contains two extracellular immunoglobulin (Ig) domains; however, the receptor for B7-H6, located on natural killer (NK) cells, was not consistent with other B7 family member receptors, which are located on activated T cells. The receptor for B7-H6 is natural cytotoxicity triggering receptor 3 (NKp30) (1-3). NK cells are large granular lymphocytes that produce chemokines and cytokines, and participate in the inflammatory and adaptive immune response (4). NK cells are also an important part of the innate immune system as they directly kill transformed and virally infected cells (5).B7 family members serve an essential role in regulating the immune response against transformed cells through a variety of mechanisms (6). As specific niches of B7 family members continue to be dissected, their diagnostic and therapeutic potential in tumors is becoming more apparent (6,7), and this was highlighted in 2011 by the US Food and Drug Administration approval of an antibody targeting programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 in cancer (8,9). The ability to successfully target cell cycle checkpoint regulators has since led to multiple clinical trials investigating antibodies targeting the signaling pathway that the B7 family participate in (10).B7-H6 binds to NKp30, triggering antitumor NK cell cytotoxicity and cytokine secretion, thus B7-H6 functions as a tumor-ind...

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Section: Percentage Of Patients -------------------------------------mentioning

confidence: 61%

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

Sun

Hong

et al. 2017

Oncology Letters

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“…12,13,[17][18][19][20][21] Thus far, the expression of B7-H6 has been shown to be restricted to tumor cells and absent from normal hematopoietic cells from healthy individuals at steady state. 12,17 It is well known that B7 family members are induced on myeloid cells upon stimulation with infectious and proinflammatory stimuli.…”

Section: Discussionmentioning

confidence: 99%

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Matta

Baratin

Chiche

et al. 2013

Blood

120

128

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• B7-H6 transcripts, B7-H6 cell-surface expression, and sB7-H6 can be induced in inflammatory conditions in vitro and in vivo.• B7-H6 is expressed on proinflammatory CD141 CD16 1 monocytes in sepsis conditions and is linked to an increased mortality.B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14 1 CD16 1 proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll-like receptors or proinflammatory cytokines such as interleukin-1b and tumor necrosis factor a. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14 1 CD16 1 monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions. This trial was registered at www.clinicaltrials.gov as #NTC00699868. (Blood. 2013;122(3):394-404)

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“…Aggregates and/or higher molecular weight contaminants were removed by gel filtration chromatography as described earlier. 36 …”

Section: Methodsmentioning

confidence: 99%

The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells

Staudinger

Glorius

Burger

et al. 2014

Blood Cancer Journal

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Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). HM1.24-ETA′ inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA′ efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA′ was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors.

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Mimicking an Induced Self Phenotype by Coating Lymphomas with the NKp30 Ligand B7-H6 Promotes NK Cell Cytotoxicity

Cited by 48 publications

References 46 publications

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells

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