Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients

Semeraro, Michaela; Rusakiewicz, Sylvie; Minard‐Colin, Véronique; Delahaye, Nicolas; Enot, David; Vély, Frederic; Marabelle, Aurélien; Papoular, Benjamin; Pipéroglou, Christelle; Ponzoni, Mirco; Perri, Patrizia; Tchirkov, Andréï; Matta, Jessica; Lapierre, Valérie; Shekarian, Tala; Valsesia‐Wittmann, Sandrine; Commo, Frédéric; Prada, Nicole; Poirier-Colame, Vichnou; Bressac, Brigitte; Cotteret, Sophie; Brugières, Laurence; Farace, Françoise; Chaput, Nathalie; Kroemer, Guido; Valteau‐Couanet, Dominique; Zitvogel, Laurence

doi:10.1126/scitranslmed.aaa2327

Cited by 128 publications

(138 citation statements)

References 56 publications

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“…27 Semeraro M et al demonstrated that serum concentration of soluble B7-H6 correlated with the downregulation of NKp30, bone marrow metastases and chemoresistance of high-risk neuroblastoma (HR-NB), and they also indicated that soluble B7-H6 contained in the serum of HR-NB patients inhibited NK cell functions in vitro. 28 Together, our results support a notorious role of B7-H6 in the progression of certain types of cancer. Hence, we conclude that the outcome of B7-H6 expression might vary by cancer type.…”

Section: Discussionsupporting

confidence: 62%

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

Shen

Wang

et al. 2016

OncoImmunology

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The B7 gene family has crucial roles in the regulation of adaptive cellular immunity. In cancer, deregulation of co-inhibitory B7 molecules is associated with reduced antitumor immunity and cancer immune evasion. FDA approval of cancer immunotherapy antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1)-both ligands of the B7 family-demonstrate the impact of these checkpoint regulators in cancer. Using data from cBioPortal, we performed comprehensive molecular profiling of the 10 currently known B7 family proteins in 105 different cancers. B7 family members were amplified in breast cancer: with B7 mRNA levels upregulated in a cohort of 1,098 patients with all types of breast cancer and in 82 patients with triple-negative breast cancer. Promoter methylation analysis indicated an epigenetic basis for deregulation of certain B7 family genes in breast cancer. Moreover, patients with B7-H6 genomic alterations had significantly worse overall survival, and certain clinical attributes were associated with B7-H6 expression, which indicates that B7-H6 may be a potential target for breast cancer immunotherapy. Finally, using network analysis (based on data from cBioportal), we identified BTLA, MARCH8, PLSCR1 and SMAD3 as potentially involved in T cell signaling under regulation of B7 family proteins.

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Section: Discussionsupporting

confidence: 62%

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

Shen

Wang

et al. 2016

OncoImmunology

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“…6,7 NKp30 possesses alternatively spliced isoforms, which are of prognostic value for patients with gastrointestinal stromal tumors 8 and for patients with high risk neuroblastoma responding to induction chemotherapy. 9 Intriguingly, the initially described ligands for NKp30, the human cytomegalovirus pp65 tegument protein 10 and the HLA-B-associated transcript 3 (BAT3) protein 11 , were both intracellular proteins. B7-H6 (Natural cytotoxicity triggering receptor 3 ligand 1, NCR3LG1) was the first NKp30-ligand identified being a transmembrane protein expressed on tumor cell surfaces.…”

Section: Introductionmentioning

confidence: 99%

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

et al. 2016

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Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses. Using luciferase reporter assays and chromatin immunoprecipitation we mapped a functional binding site for Myc, a proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter. Pharmacological inhibition or siRNA/shRNAmediated knock-down of c-Myc or N-Myc significantly decreased B7-H6 expression on a variety of tumor cells including melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines from different origin and primary tumor tissues of hepatocellular carcinoma (HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc in tumor cells impaired NKp30-mediated degranulation of NK cells was observed. Thus, our data imply that Myc driven tumors could be targets for cancer immunotherapy exploiting the NKp30/B7-H6 axis.

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“…Quantification of serum concentration of soluble B7-H6, ligand of NKp30 activation molecule, correlated with the downregulation of NKp30, bone marrow metastasis, and chemoresistance [14]. Thus, interaction between NKp30 and B7-H6 may contribute to neuroblastoma immunosurveillance and both NKp30 expression on circulating NK cells and the serum concentration of soluble B7-H6 may represent biomarkers for risk stratification [14].…”

Section: Immunotherapy Of Neuroblastomamentioning

confidence: 99%

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

Shekarian¹,

Valsesia‐Wittmann²

2017

Neuroblastoma - Current State and Recent Updates

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Neuroblastoma (NB) is one of the major challenges of pediatric oncology with a 5-year survival rate of less than 40% despite intense therapy. The aggressiveness of the disease has been recently correlated to the degree of myeloid cells infiltrating the tumor. Together with the tumor cells and immunosuppressive cytokines (e.g., IL-10 and TGF-β), these cells hamper the generation of an efficient antitumor immune response and, therefore, favor tumor growth and metastasis. Novel therapeutic approaches are designed to target immune cells instead of cancer cells. To improve their efficacy, recent cancer immunotherapy strategies have focused on the depletion, blockade, or reprogramming of these tolerogenic immune effectors. Therefore, the principal clinical challenge is currently to identify therapeutic strategies which could overcome the primary and secondary resistances to these cancer immunotherapies. In this review, we discuss the dialogue of immune microenvironment of neuroblastoma and the immunotherapeutic strategies to cure neuroblastoma.

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Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients

Cited by 128 publications

References 56 publications

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

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