Normal Tissue Depresses While Tumor Tissue Enhances Human T Cell Responses In Vivo to a Novel Self/Tumor Melanoma Antigen, OA1

Abstract

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.

MHC Class I–Associated Phosphopeptides Are the Targets of Memory-like Immunity in Leukemia

“…Immunity to cancer-testis antigens is generally not present in healthy individuals, and becomes detectable in patients with cancer, but is associated with a poor prognosis ( 38, 39 ). Immunity to tissue-associated differentiation antigens, particularly those defined as targets for melanoma-specific T-cells, is also elevated in melanoma patients ( 40, 41 ), but is believed to be compromised by self-tolerance ( 42, 43 ). Importantly, none of the healthy donors in which these memory-compartment associated immune responses were evident showed any signs of autoimmune disease.…”

High-avidity Autoreactive CD4+ T Cells Induce Host CTL, Overcome Tregs and Mediate Tumor Destruction

“…The immunologic effects of self-antigen expression on MHC class I and II-restricted T cell frequency, avidity and function have been demonstrated in murine models involving germline antigen loss to the MDA's gp100 and Tyrosinase (26, 27), and in a human model involving the MDA OA1 (ocular albinism I) (28). Based on the compelling data shown by these antigen knockout studies, we felt that TRP-1 was a highly relevant experimental self-antigen, uniquely suitable for experiments focused on CD4-based tumor immunity, autoimmunity and self-tolerance.…”

Peptide-Based Anticancer Vaccines: Recent Advances and Future Perspectives

“…One reason might be the relative non-immunogenicity of most TAA, although immunogenicity is not exclusively an intrinsic feature of an antigen as it also depends on the level of TAA exposure to the immune system of an organism [190]. To address this issue, investigators have reported that immunization with a xenogeneic homologue of TAA or an allogeneic cell vaccine genetically modified to express alpha(1,3)galactosyltrasferase (a xenotransplantation antigen) overcame immune tolerance to weakly immunogenic self antigens and controlled tumor growth in animals [191][192][193][194].…”