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

Adham S Bear1,2, Tatiana Blanchard3, Joseph Cesare4

  • 1Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. adham.bear@pennmedicine.upenn.edu.

Nature Communications
|July 17, 2021
PubMed

Insights

This study identifies specific mutant KRAS (mKRAS) peptides as targets for cancer immunotherapy. These validated mKRAS epitopes enable T cell-based therapies to effectively eliminate tumors, offering a new avenue for treating lethal cancers.

Area of Science:

  • Oncology
  • Immunology
  • Genomics

Background:

  • Activating RAS missense mutations, particularly mutant KRAS (mKRAS), are key drivers of oncogenesis in major lethal human cancers.
  • Targeting mKRAS immunologically holds promise, but mKRAS-specific epitopes are not well-defined.

Purpose of the Study:

  • To characterize HLA class I-restricted mKRAS epitopes using a multi-omics approach.
  • To validate mKRAS peptides as immunogenic epitopes for therapeutic development.

Main Methods:

  • Multi-omics analysis to identify and characterize mKRAS epitopes.
  • Proteomic analysis to confirm epitope processing and presentation.
  • Isolation of mKRAS-specific T cell receptor (TCR) alpha/beta chains.
  • In vitro T cell cytotoxicity assays and in vivo xenograft models.

Main Results:

  • Proteomic evidence demonstrated mKRAS epitope processing and presentation by common HLA class I alleles.
  • Identified immunogenic mKRAS epitopes enabled isolation of mKRAS-specific TCRs.
  • TCR-engineered CD8+ T cells exhibited potent cytotoxicity against mKRAS tumor cell lines, with activity correlating to peptide-HLA complex abundance.
  • Adoptive transfer of engineered T cells eradicated metastatic lung cancer in a xenograft model.

Conclusions:

  • This study validates mKRAS peptides as functional epitopes for cancer immunity.
  • These findings support the development of novel immune therapies targeting mKRAS oncoprotein in various cancers.
  • The characterized epitopes and TCRs provide a foundation for mKRAS-directed cancer immunotherapy.

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