UTILIZATION OF AN ALTERNATIVE OPEN READING FRAME OF A NORMAL GENE IN GENERATING A NOVEL HUMAN CANCER ANTIGEN

Tumor infiltrating lymphocytes (TILs) derived from tumor-bearing patie nts recognize tumor-associated antigens presented by major histocompat ibility complex (MHC) class I molecules. The infusion of TIL586 along with interleukin (IL) 2 into an autologous patient with metastatic mel anoma resulted in the objective regression of tumor. A gene encoding a tumor anti-recognized by TIL586 was recently isolated and shown to en code gp75. Here we report that an antigenic peptide, MSLQRQFLR, recogn ized by TIL586 was not derived from the normal gp75 protein. Instead, this nonamer peptide resulted from translation of an alternative open reading frame of the same gene. Thus, the gp75 gene encodes two comple tely different polypeptides, gp75 as an antigen recognized by immunogl obulin G antibodies in sera from a patient with cancer, and a 24-amino acid product as a tumor rejection antigen recognized by T cells. This represents the first demonstration that a human tumor rejection antig en can be generated from a normal cellular gene using an open reading frame other than that used to encode the normal protein. These finding s revealed a novel mechanism for generating tumor antigens, which may be useful as vaccines to induce tumor-specific cell-mediated immunity against cancer.