Fetal Thymic Expression Defines the Immunogenicity of Tumor Associated Antigens

ABSTRACT Tumor associated antigens (TAAs) are promising targets for cancer immunotherapy, yet their immunogenicity varies widely and remains poorly understood. Here, we show that the immunogenic potential of TAAs is largely shaped by their expression in the thymus, likely established during fetal development. By integrating single-cell transcriptomic data across fetal and postnatal thymic epithelial cells (TECs), we find that TAA expression in fetal TECs predicts both in vitro CD8⁺ T cell immunogenicity and the immune pressure against TAAs that occurs clinically in patients treated with immune checkpoint inhibitors. Notably, CD8⁺ T cells recognizing TAAs highly expressed in the fetal thymus exhibit attenuated transcriptional, signaling, and metabolic responses even in the naïve state, consistent with a tolerogenic imprinting imparted during thymic development and selection. Further, fetal thymic expression of TAAs can be leveraged to prioritize candidate targets for therapeutic use. These findings provide a biologic basis for the extreme variability seen in TAA immunogenicity and define guiding principles for rational antigen selection to drive the next generation of effective TAA-targeted immunotherapies.