Next Article in Journal
BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers
Next Article in Special Issue
Adapter Chimeric Antigen Receptor (AdCAR)-Engineered NK-92 Cells for the Multiplex Targeting of Bone Metastases
Previous Article in Journal
Strategies for Cancer Immunotherapy Using Induced Pluripotency Stem Cells-Based Vaccines
Article

An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma

1
Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
2
Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy
3
Department of Medical Sciences and Human Oncology, “Aldo Moro” University of Bari and Policlinico Consorziale, 70124 Bari, Italy
4
Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
5
Division of General Surgery, ASST Fatebenefratelli—Sacco, 20131 Milan, Italy
6
Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy
7
Division of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
8
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
9
Immunohematology and Transfusion Service, Centre of Transplantation Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
10
Innate Pharma, 13009 Marseille, France
11
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Present address: Emergence Therapeutics, 13009 Marseille, France.
Cancers 2020, 12(12), 3583; https://doi.org/10.3390/cancers12123583
Received: 12 November 2020 / Revised: 26 November 2020 / Accepted: 27 November 2020 / Published: 30 November 2020
(This article belongs to the Special Issue Natural Killer Cells in Cancers)
Primary liver cancer is one of the most common causes of cancer-related deaths worldwide. The present study shows that the cytokine IL-15 and a humanized antibody specific for a ligand recognized by a major activating receptor (NKG2D) expressed by a subset of lymphocytes named natural killer (NK) cells can restore dysfunctional NK cell responses in patients affected by the most common liver cancer hepatocellular carcinoma. This study emphasizes the importance of NK cells for immune responses to hepatocellular carcinoma and identifies the NKG2D activating receptor/ligand axis as a possible target for immunotherapeutic interventions. More importantly, building upon previously published studies, these findings provide a basis for the future treatment of tumors unresponsive to current therapies.
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. View Full-Text
Keywords: natural killer cells; HCC; sorafenib; immunotherapy; innate immunity natural killer cells; HCC; sorafenib; immunotherapy; innate immunity
Show Figures

Graphical abstract

MDPI and ACS Style

Mantovani, S.; Varchetta, S.; Mele, D.; Donadon, M.; Torzilli, G.; Soldani, C.; Franceschini, B.; Porta, C.; Chiellino, S.; Pedrazzoli, P.; Santambrogio, R.; Barabino, M.; Cigala, C.; Piccolo, G.; Opocher, E.; Maestri, M.; Sangiovanni, A.; Bernuzzi, S.; Lhospice, F.; Kraiem, M.; Mondelli, M.U.; Oliviero, B. An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma. Cancers 2020, 12, 3583. https://doi.org/10.3390/cancers12123583

AMA Style

Mantovani S, Varchetta S, Mele D, Donadon M, Torzilli G, Soldani C, Franceschini B, Porta C, Chiellino S, Pedrazzoli P, Santambrogio R, Barabino M, Cigala C, Piccolo G, Opocher E, Maestri M, Sangiovanni A, Bernuzzi S, Lhospice F, Kraiem M, Mondelli MU, Oliviero B. An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma. Cancers. 2020; 12(12):3583. https://doi.org/10.3390/cancers12123583

Chicago/Turabian Style

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 U.; Oliviero, Barbara. 2020. "An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma" Cancers 12, no. 12: 3583. https://doi.org/10.3390/cancers12123583

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop