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PreprintCited by 4Immunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkersvaccines and immunoinformatics approaches

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Distinct sets of molecular characteristics define tumor-rejecting neoantigens

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Adams, Anngela C., Macy, Anne M., Borden, Elizabeth S., Herrmann, Lauren M., Brambley, Chad A., Ma, Tao, Li, Xing, Hughes, Alysia, Roe, Denise J., Mangold, Aaron R., Buetow, Kenneth H., Wilson, Melissa A., Baker, Brian M., Hastings, Karen Taraszka·2024·Journal for ImmunoTherapy of Cancer
DOI 10.1101/2024.02.13.579546PMC PMC12548620

Preprint — published as 10.1136/jitc-2025-013148 · Paper page

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Abstract

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

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Metadata

Authors
Adams, A. C., Macy, A. M., Borden, E. S., Herrmann, L. M., Brambley, C. A., Ma, T., Li, X., Hughes, A., Roe, D. J., Mangold, A. R., Buetow, K. H., Wilson, M. A., Baker, B. M., & Hastings, K. T.
Affiliations
  • Phoenix VA Health Care System (US)
  • University of Notre Dame (US)
  • Mayo Clinic (US)
  • Mayo Clinic in Arizona (US)
  • University of Arizona (US)
  • Arizona State University (US)
Corresponding author
Hastings, Karen Taraszka
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
openRxiv
Published
2024-02-16
Volume
13
Issue
10
Pages
e013148-e013148
ISSN
2051-1426 (ISSN-L)
DOI
10.1101/2024.02.13.579546
PMC
PMC12548620
OpenAlex
W4415451524
Cited by
4
References
1
Citations by year
2026: 3 · 2025: 1
FWCI
1.48
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (I01BX005336)
  • Mayo Clinic
  • Dermatology Foundation
  • American Skin Association
  • Arizona State University
  • University of Arizona
  • National Institutes of Health (75N93020D00005, 75N99020D00005)
  • National Heart, Lung, and Blood Institute (75N92020D00005)
  • National Institute on Drug Abuse (75N95020D00005)
  • National Cancer Institute (T32CA009213, P01CA229112, F30CA281056, F30CA257622, P30CA023074)
  • National Institute of General Medical Sciences (R35GM118166)
  • National Institute of Allergy and Infectious Diseases (75N93023D00005, 75N93022D00005)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
cutaneous squamous cell carcinoma, neoantigen vaccines, personalized cancer vaccines, MHC class I binding, T cell receptor recognition, mutational signatures, driver mutations, CD8+ T cells

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