The long-term objective of this research is to dissect the tumor-specific antigenicity into its multiple separate components, so that we can determine the functional and molecular relationship of the antigens. To do this, tumor-specific T-cell clones and monoclonal antibodies will be used to select for tumor variants that express defined antigenic components. By consecutive cycles of selection for variants, the size of the antigenic repertoire of independently segregating unique tumor antigens will be determined. The frequency of antigen loss variants will be analyzed, and it will be established by fluctuation and analysis whether antigen loss is due to mutation or regulation. Monoclonal antibodies will be generated which have unique specificity for variants expressing T-cell-defined components. If a cytolytic or helper T-cell clone and a monoclonal antibody recognize the same unique antigen, then either of the two probes should select For variants that have specifically lost sensitivity to both probes. If possible, the T-cell recognition of the antibody-defined unique tumor antigen will be confirmed using L cells that have been transfected with genes coding for the unique tumor-specific antigen. Finally, the nature and molecular independence of the unique tumor antigens recognized by the monoclonal antibodies will be determined by immune precipitation and two-dimensional gel electrophoresis to indicate whether the multiple unique antigens belong to a family of related molecules. The hierarchy of response to multiple independent tumor antigens on an individual cancer cell means that the host only responds to one or a few of the multiple antigens. Therefore, the reasons for the hierarchical recognition of immunodominant tumor antigens will be examined. A clinical objective is to devise effective immunotherapy against cancer. Immune resistance should be increased if ways can be found to induce the host to respond to the recessive antigens or if a combination of monoclonal antibodies and/or T cells can be given passively (in analogy with the use of combination chemotherapy). (AG)
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