Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens
Christine E. Nelson,
Emily A. Thompson,
Clare F. Quarnstrom,
Kathryn A. Fraser,
Davis M. Seelig,
Siddheshvar Bhela,
Brandon J. Burbach,
David Masopust,
Vaiva Vezys
Affiliations
Christine E. Nelson
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Emily A. Thompson
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Clare F. Quarnstrom
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Kathryn A. Fraser
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Davis M. Seelig
Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55118, USA
Siddheshvar Bhela
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Brandon J. Burbach
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
David Masopust
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA
Vaiva Vezys
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
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
