OLIGOPEPTIDE INDUCTION OF A CYTOTOXIC T-LYMPHOCYTE RESPONSE TO HER-2/NEU PROTOONCOGENE IN-VITRO

The HER-2/neu proto-oncogene (HER-2) encodes a transmembrane protein whose expression is enhanced in a number of breast and ovarian tumors and correlates with tumor aggressiveness. Because of its expression on normal epithelial cells, HER-2 can be defined as a tumor associated antigen and is of interest as a target of a therapeutic anti-tumor T cell response. To investigate whether oligopeptides analogs of HER-2 isolated from a likely target area of T cells can induce an anti-tumor CTL response, peripheral blood mononuclear cells were stimulated in vitro with HER-2 synthetic peptides. CTL cultures generated recognized peptides used as immunogen. A CD3(+)CD8(+)CD4(-) line isolated from these cultures lysed HLA-A2(+), HER-2(+) ovarian tumors but not natural killer target K562 cells, and showed significantly higher lysis of HER-2(high) than of HER-2(low) ovarian tumors. This lysis was inhibited by HER-2 peptide-pulsed HLA-A2(+) targets, suggesting that similar epitopes are presented on tumor cells associated with HLA-A2. The observation that peptide analogs of a proto-oncogene can induce CTL in vitro which express tumor lysis dependent on the levels of expression of HER-2 is novel for human tumor systems. Targeting by T cells of HER-2 may prove useful for understanding the mechanisms of recognition, tolerance, and therapeutic use of human tumor reactive T cells. (C) 1994 Academic Press, Inc.