Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma
Beth E. Grace, Coralie M. Backlund, Duncan M. Morgan, Byong H. Kang, Nishant K. Singh, Brooke D. Huisman, C. Garrett Rappazzo, Kelly D. Moynihan, Laura Maiorino, Connor S. Dobson, Taeyoon Kyung, Khloe S. Gordon, Patrick V. Holec, Overbeck C. Takou Mbah, Daniel Garafola, Shengwei Wu, J. Christopher Love, K. Dane Wittrup, Darrell J. Irvine, Michael E. Birnbaum
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.