AUTHOR=Grace Beth E. , Backlund Coralie M. , Morgan Duncan M. , Kang Byong H. , Singh Nishant K. , Huisman Brooke D. , Rappazzo C. Garrett , Moynihan Kelly D. , Maiorino Laura , Dobson Connor S. , Kyung Taeyoon , Gordon Khloe S. , Holec Patrick V. , Mbah Overbeck C. Takou , Garafola Daniel , Wu Shengwei , Love J. Christopher , Wittrup K. Dane , Irvine Darrell J. , Birnbaum Michael E. TITLE=Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.886683 DOI=10.3389/fimmu.2022.886683 ISSN=1664-3224 ABSTRACT=

While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+ T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8+ T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.