Tracking the common ancestry of antigenically distinct cancer variants

In the months and years after first diagnosis, cancers often show an increa se in their malignancy such as faster growth, resistance to chemo- and/or h ormonal therapy, and loss of antigens targeted by immunotherapy, Our object ive 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 emer gence of previously hidden antigens, or the acquisition of new tumor-specif ic antigens, In this study, we used the primary UV-induced murine tumor 810 1, which consists predominantly of regressor tumor cells that express the i mmunodominant mutant p68 antigen, but this tumor also contains progressor v ariants that have lost this antigen. To search for tumor-specific antigens on the immune escape progressors, we raised CD8(+) T cells specific for the se variants. We found that one of the escape variants expressed a previousl y unrecognized, unique tumor-specific antigen. However, this unique antigen was not readily detectable on any of the other 8101 lines we tested. To pr ove that these antigenically distinct cancer variants had indeed been deriv ed from the same tumor and neither represented new tumors nor contamination s by other cell lines, we used unique tumor-specific p53 mutations as a lin eage-specific marker to demonstrate that these antigenically distinct progr essor variants were derived from the 8101 tumor, Because p53 mutations occu r very early during UV carcinogenesis and vary from tumor to tumor, they pr ovide convenient reliable markers for tracking the origin of cancers arisin g after immune selection or immunotherapy.