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

Article Article scientifique Article Deficient natural killer cell NKp30-mediated function and altered NCR3 splice variants in hepatocellular carcinoma eng 2018 author Mantovani Stefania author Oliviero Barbara author Lombardi Andréa 836941 author Varchetta Stefania author Mele Dalila author Sangiovanni Angelo author Rossi Giorgio author Donadon Matteo author Torzilli Guido author Soldani Cristiana author Porta Camillo author Pedrazzoli Paolo author Chiellino Silvia author Santambrogio Roberto author Opocher Enrico author Maestri Marcello author Bernuzzi Stefano author Rossello Armando author Clement Sophie 759123 author De Vito Claudio 795706 author Rubbia-Brandt Laura 31809 author Negro Francesco 96509 author Mondelli Mario U 10.1002/hep.30235 30153337 0270-9139 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. Dewey 616 Dewey 616.07 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 297 Etudes et traitement de l'hépatite C et B 554 391 Métastases du foie 657 Hepatology 4b99352a-f888-4ac9-9a5b-6a551e0dcfd6 Article (Accepted version) Restricted Article.pdf 733816 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

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Deficient natural killer cell NKp30-mediated function and altered NCR3 splice variants in hepatocellular carcinoma	Hepatology			2018	511	0

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Lombardi, Andréa