Antigenicity and immunogenicity of Melan‐A/MART‐1 derived peptides as targets for tumor reactive CTL in human melanoma

Abstract

Some cancer patients mount spontaneous T- and B-cell responses against their tumor cells. Autologous tumor reactive CD8 cytolytic T lymphocyte (CTL) and CD4 T-cell clones as well as antibodies from these patients have been used for the identification of genes encoding the target antigens. This knowledge opened the way for new approaches to the immunotherapy of cancer. In this review, we describe the characterization of the structure-function properties of the melanocyte/melanoma tumor antigen Melan-A/MART-1, the assessment of the T-cell repertoire available against this antigen in healthy individuals, and the analysis of naturally acquired and/or vaccine-induced CTL responses to this antigen in patients with metastatic melanoma.

Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

“…The average numbers of circulating A2/Melan-A tetramer + T cells enumerated ex vivo in the melanoma and vitiligo patients studied in the present paper were found to be highly comparable. These cell frequency data fit in well with our previous analyses of other HLA-A*0201 melanoma and vitiligo patients [13,14] and are in agreement with the estimates reported in the literature [5,8,9]. The in vivo priming and functional capacity of melanocyte-specific lymphocytes are important issues, since recent data suggested that Melan-Aspecific cells circulating in some melanoma patients are either ignorant (not primed) or anergic [8,23,24].…”

“…Below this threshold, CTL can still be induced but will not cause self destruction, as might occur in melanoma. A growing body of evidence suggests that the induction of at least limited autoimmune responses is desirable to efficiently eliminate cancer cells that express normal self (tumor) antigens [6][7][8][9]. Depigmentation sometimes occurring in patients with malignant melanoma, either spontaneously or more often as a result of successful immunotherapy, exemplifies such dualistic immunity.…”

“…Similarities exist between the autoimmunity observed in vitiligo and the tumor immunity observed in melanoma immuno-surveillance, as CTL directed to self antigens shared by normal melanocytes and melanoma cells are found in both conditions and imply a breakdown of tolerance [5][6][7][8][9][10]. However, the resulting immune reaction is the opposite: In vitiligo, natural immune tolerance is overridden such that the host immune system can orchestrate melanocyte destruction, whereas in melanoma, an immune effector function of potential benefit to the host, i.e.…”

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).…”

Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909

“…CpG ODNs directly stimulate DC activation through TLR9 triggering (8,9), leading to enhanced T cell responses specific for coadministered antigens in mice (10)(11)(12)(13)(14). For example, we have reported previously that addition of CpG ODNs to melanoma antigen A [26][27][28][29][30][31][32][33][34][35] peptide (Melan-A [26][27][28][29][30][31][32][33][34][35] peptide; a widely used antigenic peptide in vaccine trials of HLA-A2 + melanoma patients) mixed with incomplete Freund's adjuvant (IFA) increased Melan-A-specific T cell responses in HLA-A2 transgenic mice (15). However, the CpG motifs that stimulate the murine immune system are suboptimal for stimulating the human one.…”