A BREAST AND MELANOMA-SHARED TUMOR-ANTIGEN - T-CELL RESPONSES TO ANTIGENIC PEPTIDES TRANSLATED FROM DIFFERENT OPEN READING FRAMES

Infusion of TIL586 along with IL-2 into the autologous patient with me tastatic melanoma resulted in the objective regression of tumor. Here, we report that screening a cDNA library from the 586mel cell line usi ng CTL clones derived from TIL586 resulted in the isolation of a gene, CAG-3 (cancer Ag gene 3), Sequence analysis revealed that CAG-3 encod es an open reading frame identical to NY-ESO-1, which was recently rep orted to be recognized by autologous serum from a patient with esophag eal cancer. Thus, NY-ESO-1 appears to be an immune target for both Ab- and T cell-mediated responses. Significantly, NY-ESO-l-specific CTL c lones were capable of recognizing two HLA-A31-positive fresh and cultu red breast tumors. To our knowledge, this represents the first direct demonstration that tumor-specific CTL clones can recognize both breast and melanoma tumor cells. A 10-mer antigenic peptide ESO10-53 (ASGPGG GAPR) was identified from the normal open reading frame of NY-ESO-1 ba sed on its ability to sensitize HLA-A31-positive target cells for cyto kine release and specific lysis, Interestingly, two additional CTL clo nes that were sensitized with NY-ESO-1 recognized two overlapping anti genic peptides derived from an alternative open reading frame of the s ame gene. These findings indicate that CTLs simultaneously responded t o two different gene products translated from the normal and alternati ve reading frames of the same gene. Understanding of this mechanism by which the alternative reading frame is translated may have important implications in tumor immunology.