A unique tumor antigen produced by a single amino acid substitution

PA Monach, SC Meredith, CT Siegel, H Schreiber - Immunity, 1995 - cell.com
PA Monach, SC Meredith, CT Siegel, H Schreiber
Immunity, 1995cell.com
Mice immunized against a cancer recognize antigens unique to that cancer, but the
molecular structures of such antigens are unknown. We isolated CD4+ T ceil clones
recognizing an antigen uniquely expressed on the UV-induced tumor 6132A; some clones
inhibited the growth of tumors bearing the specific antigen. AT ceil hybridoma was used to
purify this antigen from nuclear extracts by RP-HPLC and SDS-PAGE using T ceil
immunobiot assays. A partial amino acid sequence was nearly identical to a sequence in …
Summary
Mice immunized against a cancer recognize antigens unique to that cancer, but the molecular structures of such antigens are unknown. We isolated CD4+ T ceil clones recognizing an antigen uniquely expressed on the UV-induced tumor 6132A; some clones inhibited the growth of tumors bearing the specific antigen. A T ceil hybridoma was used to purify this antigen from nuclear extracts by RP-HPLC and SDS-PAGE using T ceil immunobiot assays. A partial amino acid sequence was nearly identical to a sequence in ribosomal protein L9. The cDNA sequence of L9 from 6132A PRO ceils differed from the normal sequence at one nucieotide; this mutation encoded histidine instead of ieucine at position 47. A synthetic peptlde containing this mutation was over lOOO-fold more stimulatory of T cells than was the wild-type peptide. These results indicate that this unique tumor antigen is derived from a single amino acid substitution in a cellular protein. introduction
T lymphocytes from many cancer patients display at least rudimentary reactivity against the malignancies of the hosts. Recently, several shared tumor antigens recognized by these T cells or by T cells from mice immunized with cancer cells have been identified at the molecular level (Van der Bruggen et al., 1991; Van den Eynde et al., 1991; Brichard et al., 1993; Gaugler et al., 1994; Bakker et al., 1994; Kawakami et al., 1994; Mandelboim et al., 1994). Each of these antigens has also been found in other tumors or cell lines similar in origin to the tumor from which the antigen was isolated; occasionally, the antigens are expressed by cancers from different lineages as well. In general, the proteins are known to be identical to their counterparts in normal tissues. The above findings on shared tumor antigens cannot, however, account for the results of experiments that explored acquisition of immunity to tumors: immunization of animals against tumors usually confers specific immunity against that particular tumor and not others, even those of the same tissue type induced with the same carcinogen (Prehn and Main, 1957; Pasternaketal., 1964; Basombrio, 1970; Kripke, 1974; for review see Srivastava and Old, 1966). Such specificity indicates the existence of “unique” or individually distinct tumor transplantation antigens, as opposed to “shared” or tumor-associated transplantation antigens. The diversity of unique tumor antigens is so strik-
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