Normal tissue depresses while tumor tissue enhances human T cell responses in vivo to a novel self/tumor melanoma antigen, OA1.
Antitumor T cells often recognize targets that are nonmutated "self" tissue differentiation Ags, but the relative impact of Ag expression by normal and transformed tissue for a human self/tumor Ag has not been studied. To examine the influence of self-tolerance mechanisms on the function of self/tumor-specific T cell responses in humans, we sought to identify an Ag that was expressed, processed, and presented in an MHC-restricted fashion by tumor cells, but for which there was the human equivalent of a "knockout." In this study, we report the first immunological characterization of a melanoma/melanocyte differentiation Ag, called OA1, which meets these criteria. This Ag, an X chromosome-encoded melanoma/melanocyte differentiation Ag, was completely deleted in a male patient. Using a newly identified HLA-A*2402-restricted epitope (LYSACFWWL) to study T cell tolerance, we found that OA1-specific T cell reactivity was more than five SD higher in the knockout patient that in normal controls. These data provide compelling evidence for T cell tolerance to OA1 in humans. Most surprisingly, we found elevated levels of OA1-specific T cells in patients with metastatic malignant melanoma, indicating that the tumor-bearing state partially reversed tolerance observed in normal (non-"knockout") individuals. Taken together, these findings indicated that tolerance can exist for self/tumor Ags in humans, and that this tolerance could be partially abrogated by the growth of the tumor, increasing the reactivity of tumor Ag-specific T cells. Thus, the tumor-bearing state reverses, in part, the tolerance of T cells that results from the normal expression of tissue differentiation Ags.
Touloukian
Christopher E
CE
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Leitner
Wolfgang W
WW
Schnur
Rhonda E
RE
Robbins
Paul F
PF
Li
Yong
Y
Southwood
Scott
S
Sette
Alessandro
A
Rosenberg
Steven A
SA
Restifo
Nicholas P
NP
D017951:Antigen Presentation / Q000235:genetics; D000951:Antigens, Neoplasm; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D005136:Eye Proteins / Q000235:genetics / Q000276:immunology*; D014644:Genetic Variation / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D000951:Antigens, Neoplasm; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D005136:Eye Proteins; C095276:GPR143 protein, human; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins