Robust Iterative Stimulation with Self-Antigens Overcomes CD8⁺ T Cell Tolerance to Self- and Tumor Antigens

The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8⁺ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8⁺ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8⁺ T cells that can be used for cancer treatment.