Man Interleukin 15 Eukaryotic Gene Expression And Gene Therapy, Lung Adenocarcinoma In Mice

Interleukin (IL)-15 shares IL-2 receptor β and γ chains and resembles IL-2 in multiple biological activities. IL-15 could induce the T, B and NK cell proliferation and differentiation, promote the CTL/NK cytotoxicity, and may have more potent antitumor activities than IL-2. In this study, we aim at further investigating the gene therapeutic efficacy to murine lung adenocarcinoma by the human (h) IL-15 gene modified tumor cells and the naked IL-15 expressing plasmid DNA injection as well. Our previous studies demonstrated that the tumorigenicity of the hIL-15 cDNA transfected murine lung adenocarcinoma cells LA795A in the syngeneic T739 mice was markedly reduced compared with the vacant vector transfected LA795neo cells and the wild type LA795 cells. While in BALB/c nude mice, the three cell lines grew in the same degree, which indicate that the inhibitory of the tumor growth was at least T cell dependent and the CD8⁺ CTL involved might be a major effector. In present study, It was further found that the survival rate of the T739 mice inoculated with LA795A tumor cells was much higher than rates of ones inoculated with LA795neo or LA795 cells and the maximum survival time was prolonged 20 days. Moreover, vaccinations with the ⁶⁰Co irradiated LA795A, LA795neo and LA795 cells could partially protect the mice from subsequent LA795 cells attack. The tumor growth in T739 mice was significantly inhibited by such vaccination, even not completely abrogated. The CTL and NK cytotoxicity of the splenocytes obtained from this model were both markekdly enhanced, but especially in case of NK activity. The MHC class I molecules on the tumor cells were maintained or reduced to a very low level after the IL-15 gene modification, implying that the tumor cells were cross-presented to the CD8⁺T cell by the host antigen presenting cells (APCs). The IL-15 gene modified tumor cells might enhance the cross-priming of CD4⁺ T and CD8⁺ T cells to increase the CTL cytotoxicity, or selectively stimulate the memorial phenotype CD44^hiCD8⁺ T cell proliferation and promote the memorial CTL function. More importantly, down-regulation of class I MHC molecules on tumor cells could release the inhibiton of NK and several CD8⁺ T cells, due to interaction between inhibitory receptors (KIRs) and low expressed class I moleule. So the poorly expressed MHC class I molecules on tumor cells could be more sensitive to NK cell lysis, which would account for the significant elevation of NK activity after the LA795A therapy. The in vitro NK cytotoxicity assay of human PBMCs to PG, PGneo and PG1 tumor cells further confirmed our hypothesis, that the PG1 cells were much more easily to be killed by NK cells in comparison with the MHC I...