C-myc oncogene expression has been implicated in the poor prognosis of human renal cell carcinoma (RCC), and these tumor cells are resistant to cytotoxic effector cells. We hypothesized that the resistance of RCC cells to lysis by cytotoxic effector lymphocytes might be regulated by c-myc expression. The present study tested this hypothesis by examining the effect of c-myc antisense oligonucleotide treatment on the susceptibility of RCC to lysis by cytotoxic lymphocytes. The Caki-1 human RCC cell line constitutively expresses c-myc mRNA, and treatment with c-myc antisense oligonucleotide resulted in a significant inhibition of the expression of c-myc mRNA and enhanced susceptibility to lysis by peripheral blood lymphocytes (PBL). The enhanced susceptibility to lysis was observed by PBL derived from both normal donors and patients with RCC. The susceptibility of c-myc antisense oligonucleotide-treated Caki-1 cells to lysis by lymphokine-activated killer (LAK) cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes (TIL) was also enhanced. Furthermore, enhanced susceptibility was also seen when freshly isolated autologous tumor cells were used as target cells. The mechanism of the enhanced susceptibility of c-myc antisense oligonucleotide-treated Caki-1 cells to lysis was examined. No effect was observed on the expression of major histocompatibility complex (MHC) class I and MHC class II on the tumor cells. However, there was a modest increase in the frequency of effector-target binding. Further, c-myc antisense oligonucleotide-treated Caki-1 cells were more susceptible to lysis by tumor necrosis factor-α (TNF-α). The findings of this study demonstrate that c-myc antisense oligonucleotide directly affects established RCC cells and freshly isolated RCC cells by rendering them more susceptible to lysis by PBL, LAK cells, NK cells, and T lymphocytes. The enhanced susceptibility may be due in part to the enhanced sensitivity to TNF-α and to the augmentation of PBL binding to tumor cells. The possible clinical implications of these findings are discussed.
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