Recognition of Shared Melanoma Antigens in Association With Major HLA-A Alleles by Tumor Infiltrating T Lymphocytes From 123 Patients With Melanoma

Abstract

A total of 123 tumor-infiltrating T lymphocyte (TIL) cultures established from patients with HLA-A1, -A2, -A3, -A24, or -A31 metastatic melanoma in the Surgery Branch, National Cancer Institute, were screened for recognition of shared melanoma antigens including five melanosomal proteins (tyrosinase, MART-1/melan-A, gp100, TRP1, TRP2) as well as peptides derived from MAGE-1 and MAGE-3. Examination of the specificity of these T cells indicated that 16% of HLA-A1 TIL, 57% of HLA-A2 TIL, 7% of HLA-A3 TIL, 13% of HLA-A24 TIL, and 27% of HLA-A31 TIL recognized shared melanoma antigens restricted by major histocompatibility complex class I. Melanosomal proteins were frequently recognized by these TIL, and MART-1(27-35), gp100(154-162), gp100(209-217), and gp100(280-288) represent highly immunogenic epitopes that were recognized by a high percentage of HLA-A2 restricted melanoma reactive TIL. Recognition of gp100 by HLA-A2 restricted TIL significantly correlated with clinical response to adoptive immunotherapy with TIL in 21 HLA-A2 melanoma patients (p = 0.024). Four HLA-A1, two HLA-A2, two HLA-A3, one HLA-A24, and two HLA-A31 restricted shared antigen-specific TIL did not recognize the previously identified antigens tested in this study, and may be useful for the identification of new melanoma antigens. The observation that TILs isolated from patients with metastatic melanoma recognized melanosomal proteins in the context of predominant HLA-A alleles implies that it may be possible to develop immunotherapies for patients with melanoma expressing diverse HLA types.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Abundant data indicate that 'shared' melanocyte lineage antigens, such as tyrosinase 38 , can be recognized by T cells in patients with melanoma, particularly following investigational vaccinations [39][40][41] . Larger-scale analyses are needed to understand the full repertoire of shared and tumour-specific epitopes that can be recognized in melanomas, even in untreated patients.…”

Novel antibodies as anticancer agents

“…Among this group, many specific antigens were identified, such as NY-ESO-1 and the MAGE-1 antigens, which belong to cancer-testis family, gp100, which belongs to the differentiation antigens group, and many more (Visseren et al, 1997;Chen et al, 1998a, b;Jager et al, 1998;Pascolo et al, 2001). It is well-established that human melanoma cells express antigens that are recognized by cytotoxic T-lymphocyte (CTL) derived from cancer patients (Brichard et al, 1993;Kawakami et al, 1994;Wolfel et al, 1994;Fleischhauer et al, 1996;Pittet et al, 1999;Kawakami et al, 2000;Engelhard et al, 2002;Romero et al, 2002;Schaed et al, 2002). These are mainly differentiation antigens such as gp100, MART1 and tyrosinase, which represent a very attractive target because their expression is limited to a well-defined cell lineage (melanocytes).…”

A Single Heteroclitic Epitope Determines Cancer Immunity After Xenogeneic DNA Immunization Against a Tumor Differentiation Antigen

“…Immunity against differentiation Ags is a form of autoimmunity that can mediate destruction of tumors and normal tissues (1)(2)(3)(4)(7)(8)(9)(10)(11). In fact, tumor-infiltrating lymphocytes from patients with melanoma most often recognize melanocyte differentiation Ags (12). Previous studies have shown that xenogeneic immunization against the melanosomal differentiation Ags tyrosinase-related protein-1 TRP-1/gp75 (3,4), dopachrome tautomerase (1), and gp100/pmel 17 (2), either with DNA encoding the Ag or with recombinant protein, can result in the rejection of transplanted syngeneic melanomas in mice.…”