EBV-Induced Human CD8+ NKT Cells Suppress Tumorigenesis by EBV-Associated Malignancies

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-10, Vol.69 (20), p.7935-7944
• Main Authors: Yuling, He, Ruijing, Xiao, Li, Li, Xiang, Ji, Rui, Zhou, Yujuan, Wang, Lijun, Zhang, Chunxian, Du, Xinti, Tan, Wei, Xiao, Lang, Chen, Yanping, Jiang, Tao, Xiong, Mengjun, Wu, Jie, Xiong, Youxin, Jin, Jinquan, Tan
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Chimera - immunology; Epstein-Barr Virus Infections - immunology; Female; Flow Cytometry; Herpesvirus 4, Human - immunology; Hodgkin Disease - immunology; Hodgkin Disease - prevention & control; Hodgkin Disease - virology; Humans; Infectious diseases; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Killer Cells, Natural - immunology; Medical sciences; Mice; Mice, SCID; Nasopharyngeal Neoplasms - immunology; Nasopharyngeal Neoplasms - prevention & control; Nasopharyngeal Neoplasms - virology; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; T-Lymphocytes, Cytotoxic - immunology; Th1 Cells - immunology; Thymus Gland - immunology; Thymus Gland - metabolism; Tumors; Viral diseases
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-0828

The underlying mechanism of the protective and suppressive role of NKT cells in human tumor immunosurveillance remains to be fully elucidated. We show that the frequencies of CD8(+) NKT cells in patients with EBV-associated Hodgkin's lymphoma or nasopharyngeal carcinoma are significantly lower than those in healthy EBV carriers. These CD8(+) NKT cells in tumor patients are also functionally impaired. In human-thymus-severe combined immunodeficient (hu-thym-SCID) chimeras, EBV challenge efficiently promotes the generation of IFN-gamma-biased CD8(+) NKT cells. These cells are strongly cytotoxic, drive syngeneic T cells into a Th1 bias, and enhance T-cell cytotoxicity to EBV-associated tumor cells. Interleukin-4-biased CD4(+) NKT cells are predominately generated in unchallenged chimeras. These cells are noncytotoxic, drive syngeneic T cells into a Th2 bias, and do not affect T-cell cytotoxicity. In humanized xenogeneic tumor-transplanted hu-thym-SCID chimeras, adoptive transfer with EBV-induced CD8(+) NKT cells significantly suppresses tumorigenesis by EBV-associated malignancies. EBV-induced CD8(+) NKT cells are necessary and sufficient to enhance the T-cell immunity to EBV-associated malignancies in the hu-thym-SCID chimeras. CD4(+) NKT cells are synergetic with CD8(+) NKT cells, leading to a more pronounced T-cell antitumor response in the chimeras cotransferred with CD4(+) and CD8(+) NKT cells. Thus, immune reconstitution with EBV-induced CD8(+) NKT cells could be a useful strategy in management of EBV-associated malignancies.