SUPPRESSION OF MHC CLASS-I ANTIGENS IN ONCOGENIC TRANSFORMANTS - ASSOCIATION WITH DECREASED RECOGNITION BY CYTOTOXIC T-LYMPHOCYTES

Cytotoxic T lymphocytes (CTLs) recognize peptide fragments derived fro m endogenous proteins, processed internally, and presented at the cell surface by major histocompatibility complex (MHC) class I molecules. The use of specific CTL for cancer therapy is limited because of their dependence on effective processing and presentation of appropriate an tigenic peptides. Structural alterations, like point mutation or somat ic loss, or dysregulation of key elements in the processing or present ation pathway, may allow cells to escape the immune surveillance. Inde ed, the expression of MHC class I antigens on the surface of virus- an d oncogene-transformed cells is low and correlates with tumorigenicity . Transformation of murine fibroblasts with the ras oncogene results i n the suppression of cell surface expression of all H-2 loci as determ ined by FACScan analysis using a panel of monoclonal antibodies. We th en examined whether the oncogene-mediated suppression of MHC class I s urface expression was associated with reduced recognition of transform ants by CD8(+) T lymphocytes. Murine T lymphoma cells were stably tran sfected by the Ha-ras oncogene. The transfectants expressed distinct l evels of the Ha-ras specific protein p21. Again, immunofluorescence an alysis demonstrated an inverse correlation between oncogene and MHC cl ass I surface expression in RMAras transformants. Allogeneic H-2K(b)-r estricted cytotoxic T lymphocytes were able to efficiently lyse the pa rental T lymphoma cells. In contrast, the CTL-mediated lysis of ras tr ansformants was significantly downregulated compared with untransfecte d RMA cells. The efficiency of CTL-mediated lysis of RMAras cells was directly associated with reduced MHC class I membrane and high p21ras protein expression. Thus, the oncogene-mediated downregulation of MHC class I surface expression resulted in a reduced CTL response. Attempt s are in progress to revert the defects in MHC class I surface express ion of oncogenic transformants by introducing the different elements o f the antigen presentation pathway. Such studies will not only provide improved understanding of the mechanisms of tumor escape, but also wi ll suggest strategies to repair cellular defects in cancer patients ha ving impaired expression of MHC class I antigens.