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

• Main Authors: Christine E. Nelson, Emily A. Thompson, Clare F. Quarnstrom, Kathryn A. Fraser, Davis M. Seelig, Siddheshvar Bhela, Brandon J. Burbach, David Masopust, Vaiva Vezys
• Format: Article
• Language: English
• Published: Elsevier 2019-09-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719310782

Summary: 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. : Nelson et al. show that immune tolerance to self is not a fixed state and can be overcome with robust, iterative stimulation in the context of infection. Autoreactive CD8+ T cells expanded with this method can be co-opted to target tumors bearing shared self-antigen without associated autoimmunity. Keywords: CD8 T cell, tolerance, reversal, exhaustion, dysfunction, cancer, self-antigen, neo-antigen, resident memory, vaccination