The main objectives are to: 1) Determine whether or not decisive genetic evidence for truly tumor-specific antigens can be obtained and 2) determine the basis for the seemingly endless diversity of unique tumor-specific antigens on independently induced tumors. A new bank of 131 UV-induced and spontaneous murine tumors was isolated and autochthonous nonmalignant control cells were isolated from each original tumor-bearing host. These controls will allow the exclusion of residual heterozygosity, new germline mutations or antigenic drift as sources of error. The tumors demonstrate a wide range immunogenicity from very poorly to extremely immunogenic, which ensures that at least some of these tumors will be comparable to human cancers. Several monoclonal antibodies and/or cloned CTL probes have already been developed that react with unique tumor-specific antigens on these new tumors but not with autochthonous normal cells or second autochthonous malignancies.
The aims are to: 1) generate additional antibody and CTL probes, 2) determine by variant selection whether the unique tumor-specific antigenicity of cancer may consist of multiple genetically independent components expressed on a single malignant cell, 3) determine which unique tumor-specific antigens are lost or which are retained during tumor progression, and 4) determine the genetic origin(s) of unique tumor-specific antigens. For the last aim, several powerful but independent nov approaches are available. For determining the genetic origin(s) of CTL- defined unique antigens, insertional mutagenesis with a newly constructed with replication-deficient amphotropic virus will be used for recovering cellular flanking sequences from the CTL- selected antigen loss variants. This procedure is used to generate single copy probes for the isolation of the relevant genes from the unmutagenized tumor. For determining the genetic origins of monoclonal antibody-defined unique tumor antigens, cDNA of the particular tumor is inserted into a newly constructed mammalian expression vector followed by transfection into COS cells. Selection by panning on antibody-coated dish and finally cloning of the relevant gene after repeated cycles of selection. Comparison of the genes and their predicted amino acid sequence will indicate: 1) possible homologies with other proteins. 2) whether or not unique tumor antigens belong in a family of related genes, and 3) whether the antigens are truly tumor-specific, i.e. arise as a result of somatic mutation in the tumor or its precursor.
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