ENDOPLASMIC-RETICULUM SIGNAL SEQUENCE FACILITATED TRANSPORT OF PEPTIDE EPITOPES RESTORES IMMUNOGENICITY OF AN ANTIGEN-PROCESSING DEFECTIVE TUMOR-CELL LINE

The identification of MHC-restricted and tumour-specific cytotoxic T l ymphocytes (CTLs) provides strong evidence in support of T cell-mediat ed immune surveillance against human tumour cells. These CTLs recogniz e short peptides derived from tumour-associated antigens in conjunctio n with class I molecules expressed on tumour cells. In contrast to the se observations there are now numerous examples to suggest that a numb er of tumours escape this CTL-mediated control either by down-regulati ng accessory molecules or by blocking the intracellular processing of tumour-specific antigens. Recently a number of tumour cell lines have been identified which display a transcriptional deficiency of transpor ters associated with antigen processing (also referred to as TAP). The Epstein - Barr virus (EBV)-associated tumour, Burkitt's lymphoma (BL) , is a classic example in this category. In the present study we have restored class I-restricted antigen processing in a st. cell line by t ransfecting a minigene expression Vector encoding a CTL epitope derive d from EBV linked to an endoplasmic reticulum translocation signal seq uence. These minigene transfected BL cells were not only susceptible t o lysis by virus-specific CTL but were also capable of efficiently act ivating an antigen-specific CTL response. Interestingly, the immunogen icity of these BL cells was not affected by the significantly down-reg ulated expression of adhesion molecules such as LFA1 alpha, LFA1 beta and LFA3. These findings suggest that resistance of tumour cells to CT L-mediated immune control can be reversed if the relevant peptide epit opes are appropriately presented on the cell surface.