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

<div>Abstract<p>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-γ–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. [Cancer Res 2009;69(20):7935–44]</p></div>