Administration route- and immune cell activation-dependent tumor eradication by IL12 electrotransfer.
Injection of DNA via electric pulses into targeted tissues is referred to as electrotransfer. Intratumoral electrotransfer of the IL12 gene is more effective than intramuscular electrotransfer of the same gene in the eradication of established tumors. To understand the underlying immunological mechanisms, T cell infiltration, CTL activity, inhibition of angiogenesis, and transgene expression were analyzed using immunohistochemistry, fluorescence-based CTL analysis, Northern blot, and ELISA. In addition, the therapeutic effects of IL12 gene therapy were determined in immunocompetent, immune-cell-depleted, and immunodeficient mice. We found that intratumoral, but not intramuscular, electrotransfer of the IL12 gene induces CD8+ T cell infiltration, CTL activity, and tumor eradication. Tumor eradication by intratumoral IL12 gene electrotransfer requires both NK and T cells. The absence of either cell type will abrogate the intratumoral IL12 gene therapy-induced tumor eradication. Such a requirement explains why tumors cannot be eradicated by intramuscular electrotransfer of the IL12 gene. Only NK-cell-dependent, and not T-cell-dependent, anti-tumor effects are induced by intramuscular administration. Together, these results suggest that NK cells play an important role in both administration routes, mediating tumor growth inhibition, but T cells are specifically activated by intratumoral IL12 gene electrotransfer and not by the intramuscular route.
Li
Shulin
S
Department of Comparative Biomedical Sciences, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA 70803, USA. sli@vetmed.lsu.edu
Zhang
Lijie
L
Torrero
Marina
M
Cannon
Martin
M
Barret
Robin
R
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D045744:Cell Line, Tumor; D018274:Electroporation / Q000379:methods*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D018307:Neoplasms, Squamous Cell / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D012333:RNA, Messenger; D018664:Interleukin-12