ABSTRACT: T cells recognize tumor-derived mutated peptides presented on MHC by tumors. The recognition of these neo-epitopes leads to rejection of tumors, an event that is critical for successful cancer immunosurveillance. Determination of tumor-rejecting neo-epitopes in human tumors has proved difficult, though recently developed systems approaches are becoming increasingly useful at evaluating their immunogenicity. We have used the differential aggretope index to determine the neo-epitope burden of sarcomas and observed a conspicuously titrated antigenic landscape, ranging from the highly antigenic osteosarcomas to the low antigenic leiomyosarcomas and liposarcomas. We showed that the antigenic landscape of the tumors inversely reflected the historical T cell responses in the tumor-bearing patients. We predicted that highly antigenic tumors with poor antitumor T cell responses, such as osteosarcomas, would be responsive to T cell-based immunotherapy regimens and demonstrated this in a murine osteosarcoma model. Our study presents a potentially novel pipeline for determining antigenicity of human tumors, provides an accurate predictor of potential neo-epitopes, and will be an important indicator of which cancers to target with T cell-enhancing immunotherapy.