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Only a small portion of neoantigens prioritized by current methods elicit effective T cell responses, demonstrating the critical need for improved criteria for the prediction of tumor-rejecting neoantigens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Publicly available human cSCC datasets were used to assess the frequency of shared mutations between patients. A transplantable ultraviolet light-induced mouse model of cSCC was generated. The mutational signature and driver mutations in the mouse model were compared with human tumors. Neoantigens were prioritized in the mouse model, and tumor-rejecting neoantigens were identified through (enzyme-linked immunosorbent spot (ELISpot) and in vivo prophylactic vaccination. Binding of the neoantigens and corresponding wild-type peptides to major histocompatibility complex (MHC) class I was determined. Structural modeling of peptide:MHC complexes was performed to assess for changes in structural characteristics of the neoantigens relative to the wild-type peptides.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A minority of human cSCC tumors shared neoantigens. The mouse cSCC model recapitulated the mutational signature and driver mutations found in human disease and was constrained by CD8 T cells. Two MHC class I neoantigens were identified in the mouse model that constrained cSCC growth. One tumor-rejecting neoantigen exhibited improved MHC binding, and the other had increased solvent accessibility of the mutated residue, compared with wild-type. Across known neoantigens that do not impact MHC binding, increased exposure of the mutated residue distinguished tumor-rejecting from non-immunogenic neoantigens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Given the paucity of shared mutations, this work supports the need for personalized neoantigen vaccines in cSCC. To facilitate further discovery, we provide a clinically relevant mouse cSCC model with two defined neoantigens that mediate tumor rejection. Structural changes in the exposure of features that promote T cell receptor recognition defined tumor-rejecting neoantigens. Incorporation of structural modeling to predict changes in T cell receptor accessibility is anticipated to improve the selection of neoantigens for inclusion in personalized cancer vaccines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013148","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T02:25:13Z","timestamp":1761186313000},"page":"e013148","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Structural changes from wild-type define tumor-rejecting neoantigens"],"prefix":"10.1136","volume":"13","author":[{"given":"Anngela C","family":"Adams","sequence":"first","affiliation":[{"name":"Department of Dermatology, The University of Arizona College of Medicine Phoenix, Phoenix, Arizona, USA"},{"name":"Phoenix Veterans Affairs Health Care System, Phoenix, Arizona, 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Veterans Affairs Health Care System, Phoenix, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad A","family":"Brambley","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandip Ashok","family":"Sonar","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, The University of Arizona, Tucson, Arizona, USA"},{"name":"Arizona Center on Aging, The University of Arizona College of Medicine Tucson, Tucson, Arizona, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Qualitative Health Sciences, Mayo Clinic, Rochester, Minnesota, 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