| Summary: | Natural killer/T-cell lymphoma (NKTL) is an Epstein-Barr virus (EBV)-associated
lymphoproliferative disorder characterized by poor clinical outcomes. With its
restricted latent gene expression, the therapeutic efficiency of cytotoxic T
lymphocytes (CTL) immunotherapy is limited. We investigated the use of small molecule inhibitors decitabine, a DNA hypomethylating agent, and acyclovir, an
inhibitor of viral DNA polymerase. We hypothesized they can augment EBV gene
expression to not only potentiate CTL immunotherapy, but also induce gene
expression profiles associated with longer progression-free survival (PFS) periods in
NKTL patients. We treated NKYS and NKS1 cell lines with both small-molecule
inhibitors and subjected them to immunoblotting and real-time quantitative
polymerase chain reaction. We found that the cotreatment enhanced latent
membrane protein 1 (LMP1) expression and inhibited late lytic gene expression,
recapitulating long-PFS state. We then validated the enhanced immunogenicity of
decitabine-treated NKS1 cells with T-cell receptor mimic antibodies and
demonstrated enhanced human leukocyte antigen expression and LMP1/2 epitopes
presentation. Surprisingly, LMP1/2 epitopes showed different magnitude of
presentation. Cell proliferation and viability assays showed that the long-PFS state
induced by decitabine and acyclovir exhibited reduced proliferative capacity and
viability. These results suggest additive effects of decitabine and acyclovir in NKTL
and have potential as adjuvants in immunotherapeutic regimens.
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