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.
Deficient natural killer cell NKp30-mediated function and altered NCR3 splice variants in hepatocellular carcinoma / S. Mantovani, B. Oliviero, A. Lombardi, S. Varchetta, D. Mele, A. Sangiovanni, G. Rossi, M. Donadon, G. Torzilli, C. Soldani, C. Porta, P. Pedrazzoli, S. Chiellino, R. Santambrogio, E. Opocher, M. Maestri, S. Bernuzzi, A. Rossello, S. Clément, C. De Vito, L. Rubbia-Brandt, F. Negro, M.U. Mondelli. - In: HEPATOLOGY. - ISSN 0270-9139. - 69:3(2019 Mar), pp. 1165-1179.
|Titolo:||Deficient natural killer cell NKp30-mediated function and altered NCR3 splice variants in hepatocellular carcinoma|
|Settore Scientifico Disciplinare:||Settore MED/18 - Chirurgia Generale|
|Data di pubblicazione:||mar-2019|
|Data ahead of print / Data di stampa:||14-feb-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/hep.30235|
|Appare nelle tipologie:||01 - Articolo su periodico|
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