Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma

Abstract

<jats:p>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<jats:sup>+</jats:sup> 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 <jats:italic>in vivo</jats:italic>, engineered antigen mimotopes induced a significant expansion of CD8<jats:sup>+</jats:sup> T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells <jats:italic>in vivo</jats:italic> 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.</jats:p>