Tumor Immunology

A.L. Cox, J. Skipper, Y. Chen, R.A. Henderson, T.L. Darrow, J. Shabanowitz, V.H. Engelhard, D.F. Hunt, C.L. Slingluff, "Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines," Science, 264:716-9, 1994. (Cited in more than 60 articles through September 1995) Comments by Victor Engelhard, University of Virginia, Charlottesville The importance of this paper, according to Victor Engelhard, a professor of microbiology at the University of Virginia, is that "it was one of the first conclusive reports describing a specific tumor antigen to be recognized by cytotoxic T cells in humans. PINPOINTING PEPTIDES: Victor Engelhard's team identified a tumor antigen specific to melanoma cells. "Historically, immunologists have been alternately excited and despondent with respect to harnessing the immune system against cancer," he explains. "The area got its most recent jump start around the mid-1980s, when [Steven] Rosenberg showed that lymphocytes isolated from excised human tumors and cultured in the presence of growth factors could cause tumor regression after reinfusion into the patient. This maneuver was particularly successful with human melanoma [S.A. Rosenberg et al., New England Journal of Medicine, 319:1676-80, 1988]." Subsequently, notes Engelhard, "Craig Slingluff and others showed that cytotoxic T cells isolated from one melanoma patient could recognize melanoma tumors from other patients as long as the patients shared at least one MHC-major histocompatibility complex-molecule with the [source] patient [T.L. Darrow et al., Journal of Immunology, 142:3329-35, 1989; T. Wolfel et al., Journal of Experimental Medicine, 170:797-810, 1989]." In particular, the MHC antigen of the type HLA-A2 was associated with recognition of tumors by T cells from many different melanoma patients. MHC molecules bind to peptides that are produced by the degradation of intracellular proteins and present them to T lymphocytes as potential antigens. Therefore, the next step was to "look for melanoma-specific peptide antigens associated with HLA-A2 that were recognized specifically by the cytotoxic T cells," recounts Engelhard. By combining a mass spectrometry technique developed by Engelhard's collaborator Don Hunt and his colleagues (D.F. Hunt et al., Science, 255:1261-3, 1992), and a bioassay involving melanoma-specific T cells from several patients, the researchers attempted to pinpoint such melanoma-specific peptides. In this paper, reports Engelhard, the authors have described the identification and characterization of a peptide that could be recognized by five different sources of melanoma-specific cytotoxic T cells. The analysis of this peptide contained a few surprises for the investigators, he says. Rather than specific to melanoma cells alone, the peptide turned out to be "a fragment of a protein called gp-100 or pMel-17 that is produced by normal melanocytes in a tissue-specific manner, as well as by melanoma cells, and appears to be involved in melanin biosynthesis," he states. Since this paper was published, other groups have also reported finding that melanoma-specific antigens are derived from proteins involved in melanin biosynthesis (C.L. Slingluff et al., Current Opinions in Immunology, 6:733-40, 1994). The reason such peptides may play a role as cancer antigens, Engelhard speculates, is that "although they are part of proteins in normal cells, they have a very low affinity for the MHC molecules, and are not expressed very highly on the surface of the normal cells in association with the HLA molecules. In melanoma, we believe that the upregulation of MHC expression leads to an increase in cell-surface representation of the antigen," which allows the tumor cells to be recognized by the cytotoxic T cells. On a practical note, attempts to use these antigens as targets for cancer vaccines are under way at the University of Virginia. In fact, Engelhard contends, the potential for such applications is one of the main reasons for the popularity of this paper in the scientific community. (The Scientist, Vol:9, #21, pg.15 , October 30, 1995) (Copyright © The Scientist, Inc.)

Tumor Immunology

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