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Deficient natural killer cell NKp30-mediated function and altered NCR3 splice variants in hepatocellular carcinoma

Mantovani, Stefania
Oliviero, Barbara
Varchetta, Stefania
Mele, Dalila
Sangiovanni, Angelo
Rossi, Giorgio
Donadon, Matteo
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Published in Hepatology. 2018
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 (NKG2D) and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3 (Tim-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 siRNA-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.
PMID: 30153337
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Research groups Etudes et traitement de l'hépatite C et B (554)
Métastases du foie (657)
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MANTOVANI, Stefania et al. Deficient natural killer cell NKp30-mediated function and altered NCR3 splice variants in hepatocellular carcinoma. In: Hepatology, 2018. doi: 10.1002/hep.30235 https://archive-ouverte.unige.ch/unige:109371

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Deposited on : 2018-10-18

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