ASSOCIATION OF HER2 NEU EXPRESSION WITH SENSITIVITY TO TUMOR-SPECIFICCTL IN HUMAN OVARIAN-CANCER/

To study potential sources of tumor-associated Ags in human ovarian ca ncer, we have established two ovarian tumor cell lines (OvS1 and OvA2) from two ovarian cancer patients, which express the cellular oncogene HER2/ neu. Corresponding tumor infiltrating lymphocyte cultures have also been established and display an autologous tumor-specific pattern of cytotoxicity that is HLA-A2 restricted. To determine the potential relationship between HER2/neu expression and CTL-mediated cytolysis, we first established tumor cell clones from OvS1. These were categoriz ed as high or low expressors of HER2/neu (cOvS1(+) or cOvS1(-), respec tively), and cOvS1(+) clones displayed a significantly higher sensitiv ity to CTL killing as compared with cOvS1(-) clones. To modulate the e xpression of HER2/neu, ovarian cancer cells were treated with lFN-gamm a. After this exposure, HER2/neu expression was significantly decrease d, whereas the expression of HLA Class I was significantly increased. Despite the increase in HLA Class I molecules on the cell surface, CTL -mediated cytolysis of both OvS1 and OvA2 was significantly decreased. IFN-gamma treated cOvS1(+) clones displayed a similar decrease in sen sitivity to CTL killing, whereas IFN-gamma treated cOvS1(-) clones dis played an increase or no change in sensitivity to CTL. To confirm this apparent association between HER2/neu expression and CTL recognition, melanoma tumor cell lines that were insensitive to ovarian tumor-spec ific CTL were transfected with the HER2/neu gene. An HLA-A2(+) HER2/ne u-transfected melanoma cell line was made sensitive to HLA-A2 restrict ed ovarian tumor-specific CTL but not to HLA-A2 unrestricted CTL, wher eas an HLA-A2(-) HER2/neu-transfected melanoma remained insensitive to HLA-A2 restricted CTL. These results demonstrate that the sensitivity of ovarian epithelial tumor cells to CTL-mediated lysis is associated with the level of expression of HER2/neu, suggesting that this oncoge ne product may serve as a source of tumor-associated Ags or as an indu cer of such peptides. This is the first time in a human tumor system t hat oncogene expression has been related to the induction of antigenic ity. These results prompt us to approach new strategies for immunother apy of cancer.