LYSIS OF RAS ONCOGENE-TRANSFORMED CELLS BY SPECIFIC CYTOTOXIC T-LYMPHOCYTES ELICITED BY PRIMARY IN-VITRO IMMUNIZATION WITH MUTATED RAS PEPTIDE

Ras protooncogenes are activated by characteristic point mutations in a wide variety of malignancies. The expressed p2l(ras) proteins are oncogenic by virtue of single substituted amino acids, usually at position 12 or 61 of the 189-residue p21(ras) protein. In the current study, the ability of class I major histocompatibility complex (MHC)-restricted T cells to recognize the altered segment of a transforming p21(ras) protein and to lyse cells transformed by the corresponding ras oncogene was examined. Synthetic ras peptides encompassing the common activating substitution of leucine for glutamine at position 61 were constructed with an amino acid motif appropriate for binding to the H-2K(b) murine class I MHC molecule. Cytotoxic T lymphocytes (CTL) specific for bound ras leucine 61 peptide were elicited by in vitro immunization of normal lymphocytes with synthetic peptides. The ras peptide-induced CTL specifically lysed syngeneic fibroblasts transformed by an activated ras gene encoding oncogenic p21(ras) protein containing the same single amino acid substitution. Thus, in some circumstances, mutated p21(ras) protein can serve as a tumor-specific antigen.