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Cited by 113Immunotherapy and Immune Responsesvaccines and immunoinformatics approachesCancer Immunotherapy and Biomarkers

Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting

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Bear, Adham S., Blanchard, Tatiana, Cesare, Joseph, Ford, Michael J., Richman, Lee P., Xu, Chong, Baroja, Miren L., McCuaig, Sarah +11 more·2021·Nature Communications
DOI 10.1038/s41467-021-24562-2PMC PMC8285372
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Abstract

Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαβ isolation. TCR transfer to primary CD8+ T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8+ T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.

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  • KRAS neoantigens can act as a tumor-selective biomarker that can be targeted using engineered T-cells.

    “KRAS neoantigens can act as a tumor-selective biomarker that can be targeted using engineered T-cells [90].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [90]

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Authors
Bear, A. S., Blanchard, T., Cesare, J., Ford, M. J., Richman, L. P., Xu, C., Baroja, M. L., McCuaig, S., Costeas, C., Gabunia, K., Scholler, J., Posey, A. D., O’Hara, M. H., Smole, A., Powell, D. J., Garcia, B. A., Vonderheide, R. H., Linette, G. P., & Carreno, B. M.
Affiliations
  • Abramson Cancer Center (US)
  • University of Pennsylvania (US)
  • Philadelphia VA Medical Center (US)
  • Parker Institute for Cancer Immunotherapy (US)
Corresponding author
  • Bear, Adham S.
  • Carreno, Beatriz M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-07-16
Volume
12
Issue
1
Pages
4365-4365
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-24562-2
PMC
PMC8285372
OpenAlex
W3178086473
Cited by
113
References
14
Citations by year
2026: 10 · 2025: 34 · 2024: 22 · 2023: 23 · 2022: 22 · 2021: 2
FWCI
6.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DiRROS repository (University of Maribor) (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (IK2BX004183)
  • University of Pennsylvania (P30CA016520)
  • Parker Institute for Cancer Immunotherapy
  • National Institutes of Health (NIH-R01, CA196539, CA016520, CA009140)
  • Stand Up To Cancer
  • National Cancer Institute (T32CA009140, P01CA196539, P01CA217805, R01CA204261, U54CA232568, K12CA076931, P30CA016520)
  • National Institute of Allergy and Infectious Diseases (R01AI118891)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
mutant KRAS, HLA class I epitopes, CD8+ T cell cytotoxicity, adoptive T cell therapy, metastatic lung cancer, cancer immunotherapy
MeSH terms
Alleles, Animals, Humans, Lung Neoplasms, Mutation, Peptides, Histocompatibility Antigens Class I, Proto-Oncogene Proteins p21(ras), Receptors, Antigen, T-Cell, alpha-beta, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Adoptive Transfer, Xenograft Model Antitumor Assays, Proteomics, Cell Line, Tumor, Mice, Carcinogenesis

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