Herpes simplex virus-induced, death receptor-dependent apoptosis and regression of transplanted human cancers.

Inoculation of a live attenuated herpes simplex virus (HSV) vector, betaH1, into human U87MG glioblastoma cells transplanted into athymic nude mice induced complete regression of tumors. The infected cells underwent histochemically confirmed apoptosis without lymphocyte infiltration after expressing CD30, CD30 ligand (CD30L), tumor necrosis factor (TNF)-alpha, TNF receptor 1 (TNF-R1), FAS, and FAS ligand (FAS-L) with activation of caspases 3 and 8. Induction of the transcripts of these receptors and ligands in inoculated tumors was confirmed by quantitative RT-PCR. To examine the specificity of apoptosis in the transplanted tumor, we inoculated betaH1 into transplanted human lung, breast, gastric, and colon cancer tumors, and similar tumor regression with apoptosis was observed in all tumors. We analyzed the roles of expression of CD30, CD30L, TNF-alpha, TNF-R1, FAS, and FAS-L in the tumors, and found that HSV-induced apoptosis was suppressed by the respective antibodies. These findings indicate that the CD30/CD30L, TNF-alpha/TNF-R1, and FAS/FAS-L interactions resulted in apoptosis and tumor regression in immunocompromised mice. In addition to the death receptor-dependent apoptosis induced by HSV, the expressed ligands and receptors might enhance the susceptibility of tumor cells to cell-mediated cyto-toxicity and augment the activation of tumor-killing lymphocytes in immunocompetent models.