Association of HER2/neu expression with sensitivity to tumor-specific CTL in human ovarian cancer

Ichiro Yoshino, George E. Peoples, Peter S. Goedegebuure, Richard Maziarz, Timothy J. Eberlein

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79 Scopus citations

Abstract

To study potential sources of tumor-associated Ags in human ovarian cancer, 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 categorized as high or low expressors of HER2/neu (cOvS1+ or cOVS1-, respectively), and cOvS1+ clones displayed a significantly higher sensitivity to CTL killing as compared with cOvS1- clones. To modulate the expression of HER2/neu, ovarian cancer cells were treated with IFN-γ. After this exposure, HER2/neu expression was significantly decreased, 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-γ treated cOvS1+ clones displayed a similar decrease in sensitivity to CTL killing, whereas IFN-γ treated cOvS1- clones displayed 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-specific CTL were transfected with the HER2/neu gene. An HLA-A2+ HER2/neu-transfected melanoma cell line was made sensitive to HLA-A2 restricted ovarian tumor-specific CTL but not to HLA-A2 unrestricted CTL, whereas 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 oncogene product may serve as a source of tumor- associated Ags or as an inducer of such peptides. This is the first time in a human tumor system that oncogene expression has been related to the induction of antigenicity. These results prompt us to approach new strategies for immunotherapy of cancer.

Original languageEnglish (US)
Pages (from-to)2393-2400
Number of pages8
JournalJournal of Immunology
Volume152
Issue number5
StatePublished - Mar 1 1994

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Yoshino, I., Peoples, G. E., Goedegebuure, P. S., Maziarz, R., & Eberlein, T. J. (1994). Association of HER2/neu expression with sensitivity to tumor-specific CTL in human ovarian cancer. Journal of Immunology, 152(5), 2393-2400.