Mechanisms of escape from CD8+ T-cell clones specific for the HER-2/NEU proto-oncogene expressed in ovarian carcinomas: Related and unrelated to decreased MHC class 1 expression
✍ Scribed by Koji Kono; Eva Halapi; Christina Hising; Max Petersson; Eva Gerdin; Farkas Vanky; Rolf Kiessling
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- French
- Weight
- 208 KB
- Volume
- 70
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
We have developed an in vitro model to study mechanisms by which ovarian tumor cells that over-express the HER-2/ neu proto-oncogene escape recognition by T CD8 1 . Nine tumorspecific, HLA A2-restricted T CD8 1 clones were isolated from 2 ovarian tumor-specific T CD8 1 lines derived from tumorinfiltrating or -associated lymphocytes. Of these, 2 clones recognized the previously defined HER-2/neu epitope E75 (a.a. 369-377) and one recognized the C85 epitope (a.a. 971-979), whereas the specificity of the remaining 6 clones was unknown. Three different tumor escape variants (EVC8, EVC22 and EVC36) were produced by co-culturing an ovarian tumor line over-expressing HER-2/neu with these autologous T CD8 1 clones. Cell surface expression of HLA A2 was markedly decreased on all 3 escape variants, relative to the parental tumor line, while no significant decrease in their expression of the HER-2/neu, ICAM-1 or LFA-3 molecules was found. There was a correlation between the level of tumor-specific recognition and HLA A2 expression among the tumor clones isolated from 2 of the escape variants (EVC8 and EVC36). In contrast, high HLA A2-expressing tumor clones isolated from the EVC22 variant, or EVC22 which had regained high HLA A2 expression through IFN-g treatment, were not recognized by the HER-2/neu-specific T CD8 1 clone C-22. No mutations were found in the cDNA or the genomic DNA derived from the PCR product corresponding to a 496 bp fragment including the region coding for the E75 epitope of the HER2/neu gene in the EVC22 variant. Collectively, this in vitro model underlines the importance of decreased expression of the HLA restriction element for escape from tumor-specific T CD8 1 but also demonstrates that additional mechanisms exist. Int.