Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

Stefania Mantovani, Barbara Oliviero, Andrea Lombardi, Stefania Varchetta, Dalila Mele, Angelo Sangiovanni, Giorgio Rossi, Matteo Donadon, Guido Torzilli, Cristiana Soldani, Camillo Porta, Paolo Pedrazzoli, Silvia Chiellino, Roberto Santambrogio, Enrico Opocher, Marcello Maestri, Stefano Bernuzzi, Armando Rossello, Sophie Clément, Claudio De VitoLaura Rubbia-Brandt, Francesco Negro, Mario U. Mondelli

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Abstract

The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA–mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.

Original languageEnglish
JournalHepatology
DOIs
Publication statusPublished - Jan 1 2019

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Natural Killer Cells
Hepatocellular Carcinoma
Ligands
Natural Cytotoxicity Triggering Receptor 3
Tumor-Infiltrating Lymphocytes
Mucins
Blood Cells
Neoplasms
Protein Isoforms
Cytokines
T-Lymphocytes
Phenotype
Genes

ASJC Scopus subject areas

  • Hepatology

Cite this

@article{e64505f11ed040f194c5aad35d9febfc,
title = "Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma",
abstract = "The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA–mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.",
author = "Stefania Mantovani and Barbara Oliviero and Andrea Lombardi and Stefania Varchetta and Dalila Mele and Angelo Sangiovanni and Giorgio Rossi and Matteo Donadon and Guido Torzilli and Cristiana Soldani and Camillo Porta and Paolo Pedrazzoli and Silvia Chiellino and Roberto Santambrogio and Enrico Opocher and Marcello Maestri and Stefano Bernuzzi and Armando Rossello and Sophie Cl{\'e}ment and {De Vito}, Claudio and Laura Rubbia-Brandt and Francesco Negro and Mondelli, {Mario U.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/hep.30235",
language = "English",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",

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TY - JOUR

T1 - Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

AU - Mantovani, Stefania

AU - Oliviero, Barbara

AU - Lombardi, Andrea

AU - Varchetta, Stefania

AU - Mele, Dalila

AU - Sangiovanni, Angelo

AU - Rossi, Giorgio

AU - Donadon, Matteo

AU - Torzilli, Guido

AU - Soldani, Cristiana

AU - Porta, Camillo

AU - Pedrazzoli, Paolo

AU - Chiellino, Silvia

AU - Santambrogio, Roberto

AU - Opocher, Enrico

AU - Maestri, Marcello

AU - Bernuzzi, Stefano

AU - Rossello, Armando

AU - Clément, Sophie

AU - De Vito, Claudio

AU - Rubbia-Brandt, Laura

AU - Negro, Francesco

AU - Mondelli, Mario U.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA–mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.

AB - The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA–mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.

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U2 - 10.1002/hep.30235

DO - 10.1002/hep.30235

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JF - Hepatology

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