Pre-existing immunity to tyrosinase-related protein (TRP)-2, a new TRP-2 isoform, and the NY-ESO-1 melanoma antigen in a patient with a dramatic response to immunotherapy.
We have performed a detailed analysis of the recognition of melanoma Ags by the tumor-infiltrating lymphocytes (TIL) 1790, isolated from a patient who experienced a dramatic tumor regression following immunization with peptides from the gp100, MART-1, and tyrosinase Ags. This TIL was found to recognize HLA-A2-restricted CTL epitopes in tyrosinase-related protein (TRP)-2 (clone MR7) and NY-ESO-1 (clone M8). These epitopes were the same as the previously identified nonapeptide TRP-2: 180-188, and the overlapping NY-ESO-1 peptides, obtained by using lymphocytes from in vitro stimulation. We also cloned a previously unknown TRP-2 mRNA isoform (TRP-2-6b) that contained two novel exons alternatively spliced from the sixth intron between exons 6 and 7 of TRP-2 mRNA. The isoform encoded an HLA-A2-restricted antigenic epitope recognized by TIL clone MB4. An immunologic analysis of the patient's PBMC obtained before treatment showed the presence of high reactivity against NY-ESO-1 and both TRP-2 Ags, but not the Ags used for immunization. Because immune response against these Ags was less pronounced, it is possible that NY-ESO-1, TRP-2, and TRP-2-6b may be of importance in the generation of CTL-mediated tumor destruction and may have played a role in the dramatic tumor regression seen in this patient.
Khong
Hung T
HT
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Rosenberg
Steven A
SA
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D002469:Cell Separation; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D005260:Female; D015723:Gene Library; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000627:therapeutic use; D008565:Membrane Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000276:immunology / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000276:immunology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use; D011506:Proteins / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D018984:Epitopes, T-Lymphocyte; D007527:Isoenzymes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D011506:Proteins; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase