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 from 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 antigenic peptides. Structural alterations, like point mutation or somatic loss, or dysregulation of key elements in the processing or presentation pathway, may allow cells to escape the immune surveillance. Indeed, the expression of MHC class I antigens on the surface of virus- and oncogene-transformed cells is low and correlates with tumorigenicity. Transformation of murine fibroblasts with the ras oncogene results in the suppression of cell surface expression of all H-2 loci as determined by FACScan analysis using a panel of monoclonal antibodies. We then examined whether the oncogene-mediated suppression of MHC class I surface expression was associated with reduced recognition of transformants by CD8+ T lymphocytes. Murine T lymphoma cells were stably transfected by the Ha-ras oncogene. The transfectants expressed distinct levels of the Ha-ras specific protein p21. Again, immunofluorescence analysis demonstrated an inverse correlation between oncogene and MHC class I surface expression in RMAras transformants. Allogeneic H-2Kb-restricted cytotoxic T lymphocytes were able to efficiently lyse the parental T lymphoma cells. In contrast, the CTL-mediated lysis of ras transformants was significantly downregulated compared with untransfected 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. Attempts are in progress to revert the defects in MHC class I surface expression of oncogenic transformants by introducing the different elements of the antigen presentation pathway. Such studies will not only provide improved understanding of the mechanisms of tumor escape, but also will suggest strategies to repair cellular defects in cancer patients having impaired expression of MHC class I antigens.