An anti-mica/b antibody and il-15 rescue altered nkg2d-dependent nk cell responses in hepatocellular carcinoma

Stefania Mantovani, Stefania Varchetta, Dalila Mele, Matteo Donadon, Guido Torzilli, Cristiana Soldani, Barbara Franceschini, Camillo Porta, Silvia Chiellino, Paolo Pedrazzoli, Roberto Santambrogio, Matteo Barabino, Claudia Cigala, Gaetano Piccolo, Enrico Opocher, Marcello Maestri, Angelo Sangiovanni, Stefano Bernuzzi, Florence Lhospice, Manel KraiemMario Umberto Mondelli, Barbara Oliviero

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number3583
Pages (from-to)1-15
Number of pages15
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • HCC
  • Immunotherapy
  • Innate immunity
  • Natural killer cells
  • Sorafenib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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