Tracking the common ancestry of antigenically distinct cancer variants

In the months and years after first diagnosis, cancers often show an increase in their malignancy such as faster growth, resistance to chemo- and/or hormonal therapy, and loss of antigens targeted by immunotherapy. Our objective was to develop a model in which one can track the changes occurring as a result of in vivo immune selection, such as the loss of antigen, the emergence of previously hidden antigens, or the acquisition of new tumor-specific antigens. In this study, we used the primary UV-induced murine tumor 8101, which consists predominantly of regressor tumor cells that express the immunodominant mutant p68 antigen, but this tumor also contains progressor variants that have lost this antigen. To search for tumor-specific antigens on the immune escape progressors, we raised CD8+ T cells specific for these variants. We found that one of the escape variants expressed a previously unrecognized, unique tumor-specific antigen. However, this unique antigen was not readily detectable on any of the other 8101 lines we tested. To prove that these antigenically distinct cancer variants had indeed been derived from the same tumor and neither represented new tumors nor contaminations by other cell lines, we used unique tumor-specific p53 mutations as a lineage-specific marker to demonstrate that these antigenically distinct progressor variants were derived from the 8101 tumor. Because p53 mutations occur very early during UV carcinogenesis and vary from tumor to tumor, they provide convenient reliable markers for tracking the origin of cancers arising after immune selection or immunotherapy.