Melanoma is one of the most sudden-onset, fastest-growing, quickest-killing, least-treatable cancers known. It begins with small bluish-grayspots on the skin. These spread and multiply, but also strike inward toattack the body's visceral organs, mainly liver, lungs and brain. By thetime melanoma is fully diagnosed, there is little hope for therapy, andvirtually none for cure. Yet the disease may produce unexplainedremissions.Its inexorable course and lethality make melanoma the scourge ofoncologists. Paradoxically, these same characteristics make it theirpreferred model for studying cancer in humans. Their prime strategy isto discover the secret strategies by which the body's immune systemcounterattacks melanoma's aggression, and test experimental immunoand gene therapies.Last week, two cancer centers each reported discovering a tumor-associated antigen specific to melanoma cells. These are potentialtargets for tumor-infiltrating lymphocytes, the front-line cancer-huntingT lymphocytes. These killer T cells punch holes in cancer cells _when they can find them. Epitopes act like airport beacons that attractthe killers to their malignant target cells.Friday's Science (April 29) reported, "Identification of a PeptideRecognized by Five Melanoma-Specific Human Cytotoxic T CellLines." Scientist Craig Slingluff and his eight co-authors at theUniversity of Virginia used tandem mass spectroscopy to pinpoint andsequence one of at least nine immune-system peptides recognized bymelanoma-specific cytotoxic T lymphocytes. They picked out this verylow-abundance epitope from an estimated 10,000 species in theexperimental mixture.Killer T cells, the Science paper said, "had an exceptionally highaffinity for this nine-residue peptide," which its authors found in thetumors of five out of five end-stage melanoma patients. This multiple-recognition suggested to Slingluff that "this may be a promisingcandidate for use in peptide-based melanoma vaccines."On April 26, the National Cancer Institute's chief surgeon, StevenRosenberg reported "Cloning of the gene coding for a shared humanmelanoma antigen recognized by autologous T cells infiltrating intotumor." His paper, in the Proceedings of the National Academy ofSciences (PNAS) described a gene for a previously unknown "putativetransmembrane protein whose expression was restricted to melanomaand melanocyte cell lines and human retina," but to no other normaltissues or tumors.The NIH team named their 118-amino-acid, 13-kiloDalton discovery"MART-1," standing for "melanoma antigen recognized by T cells 1."Its expression coincided neatly with cell lysis by tumor-infiltratinglymphocytes in 10 melanoma cell lines. Of 10 normal human tissues,only retina scored positive.These two findings recall that melanoma results when the body'snormal melanocytes, which confer skin color and retinal pigment, runmalignantly amok. A non-cancerous, probably autoimmune, defect inthe melanocyte gene may cause vitiligo _ a disease of pale white skinpatches, where pigment is absent. When vitiligo occurs in a melanomapatient, clinicians take it as a sign that the immune system is fightingoff the berserk tumor cells.Rosenberg's PNAS article allowed that immune reactions inducedagainst melanocyte-melanoma lineage antigens, such as MART-1, mayalso work against healthy cells. The NIH results reported observingsome sporadic vitiligo, but no "adverse ophthalmological effectsrelated to the possible expression of these melanocyte antigens onretinal cells."Vitiligo sometimes accompanies spontaneous remissions of humanmelanoma, the Science paper noted, suggesting that "an autoimmuneresponse to melanocytes may naturally accompany the development ofimmunity to melanoma."

-- David N. Leff Science Editor

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