Melanoma Tumor Antigens

Tumor-reactive lymphocytes derived from patient peripheral blood or found to infiltrate metastatic melanoma lesions have been grown in vitro,1 permitting the cloning of melanoma antigens recognized by T cells2,3 (Table 20.1, Figure 20.1). The antigen called MAGE (melanoma antigen E) defined a family of antigens not previously identified. MAGE-1 and members of its multigene family were present on melanomas and other tumors as well as testis and placenta but no other normal tissue.4

A second group of antigens is the melanosome-related differentiation proteins. MART-1/Melan A was defined via recognition by cytotoxic T lymphocyte (CTL) clones from melanoma patient peripheral blood and by tumor-infiltrating lymphocytes (TIL).5 MART-1 is expressed by virtually all metastatic melanoma lesions, and also by melanocytes, but not normal tissue. The nonamer sequence AAGIGILTV and decamer EAAGIGILTV, representing amino acid residues 27-35 and 26-35 of MART-1, respectively, bound most strongly to human leukocyte antigen (HLA)-A2.6 These peptides stimulated the growth of specific CTL from peripheral blood mononuclear cells (PBMC) of HLA-A2-positive melanoma patients and normals.7 In a clinical study of patients with melanoma who had resected lymph nodal disease, class I peptide tetramers were employed to detect MART-1 and tyrosinase-specific CTL in tumor-infiltrating lymph nodal tissue. From 0.1% to 3% of CD8+ lymphocytes infiltrating tumor-involved lymph nodes were MART-1 specific. In contrast, the proportion of MART-1-specific cells in nontumor-containing lymph nodes was not different from background.8,9

Antigen pMel17/gp100 was defined via recognition by CTL clones from melanoma patient peripheral blood and by TIL. This 100-kilodalton (100-kDa) transmembrane glycoprotein is recognized by the HMB-45 and NKI-beteb monoclonal antibodies on melanocytes and melanoma cells.10,11 CTL clones derived from melanoma patients, and TIL grown from a melanoma patient, recognized melanoma cells that expressed gp100 in association with HLA-A2.1.12 Multiple peptides derived from gp100 that fit the consensus motif for binding to HLA-A2 were recognized by TIL from melanoma patients, including gp100 209-217 (ILDQVPSFV) and gp100 154-162 (TKTWGQYWQV), as well as gp100 457-466 (LLDGTAATLRL).1314 TIL specific for gp100 have been reported to induce regression of metastatic melanoma in patients also receiving interleukin (IL)-2) therapy.14 These data suggest that gp100 may be a relevant tumor regression antigen.

Tyrosinase is a membrane-bound protein involved in melanin synthesis15 that is expressed by virtually all primary cutaneous melanomas and by up to 90% of metastatic lesions. It encodes several epitope peptides that are presented by HLA-A2 to CTL reactive with human melanomas.16 A peptide derived from tyrosinase, amino acids 368-376, YMNGTMSQV, was shown to be posttranslationally modified by deamidation of asparagine to aspartic acid, resulting in a sequence recognized by human CTL, YMDGTMSQV, known as tyrosinase 368-376 (370D).17 The tyrosinase 368-376 (370D) peptide encodes a biologically important epitope and can induce CTL in vitro and in vivo18 (also Weber et al., unpublished data).

Recently, "cancer-testis" antigens distinct from the MAGE family, called NY-ESO-1 and SSX-2, were discovered that both elicit a strong humoral response yet encode epitope peptides recognized by CTL clones, TIL, and T helper cells

TABLE 20.1. Tumor antigens.

Tumor antigen

Specificity

Immunogenicity

Reference

Melanoma antigen E (MAGE)

MART-1/Melan A

pMel17/gp100

Tyrosinase

"Cancer testis antigen" (NY-ESO-1 and SSX-2)

Carcinoembryonic antigen (CEA) differentiation antigen

HER-2/neu

Alpha fetoprotein (AFP)

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