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An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma.
Mantovani, Stefania; Varchetta, Stefania; Mele, Dalila; Donadon, Matteo; Torzilli, Guido; Soldani, Cristiana; Franceschini, Barbara; Porta, Camillo; Chiellino, Silvia; Pedrazzoli, Paolo; Santambrogio, Roberto; Barabino, Matteo; Cigala, Claudia; Piccolo, Gaetano; Opocher, Enrico; Maestri, Marcello; Sangiovanni, Angelo; Bernuzzi, Stefano; Lhospice, Florence; Kraiem, Manel; Mondelli, Mario Umberto; Oliviero, Barbara.
Afiliação
  • Mantovani S; Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Varchetta S; Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Mele D; Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Donadon M; Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy.
  • Torzilli G; Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy.
  • Soldani C; Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy.
  • Franceschini B; Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy.
  • Porta C; Department of Medical Sciences and Human Oncology, "Aldo Moro" University of Bari and Policlinico Consorziale, 70124 Bari, Italy.
  • Chiellino S; Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Pedrazzoli P; Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Santambrogio R; Division of General Surgery, ASST Fatebenefratelli-Sacco, 20131 Milan, Italy.
  • Barabino M; Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy.
  • Cigala C; Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy.
  • Piccolo G; Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy.
  • Opocher E; Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy.
  • Maestri M; Division of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Sangiovanni A; Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  • Bernuzzi S; Immunohematology and Transfusion Service, Centre of Transplantation Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Lhospice F; Innate Pharma, 13009 Marseille, France.
  • Kraiem M; Innate Pharma, 13009 Marseille, France.
  • Mondelli MU; Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • Oliviero B; Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
Cancers (Basel) ; 12(12)2020 Nov 30.
Article em En | MEDLINE | ID: mdl-33266137
Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cancers (Basel) Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cancers (Basel) Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Itália