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.
Melanoma antigen E (MAGE)
"Cancer testis antigen" (NY-ESO-1 and SSX-2)
Carcinoembryonic antigen (CEA) differentiation antigen
Alpha fetoprotein (AFP)
Was this article helpful?
Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.