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

  • Nat Commun. 2021 Jul 16;12(1):4365. doi: 10.1038/s41467-021-24562-2.
Adham S Bear  1  2 ,  Tatiana Blanchard  3 ,  Joseph Cesare  4 ,  Michael J Ford  5 ,  Lee P Richman  6 ,  Chong Xu  3 ,  Miren L Baroja  3 ,  Sarah McCuaig  7 ,  Christina Costeas  7 ,  Khatuna Gabunia  3 ,  John Scholler  3 ,  Avery D Posey Jr  3  8  9 ,  Mark H O'Hara  10  6 ,  Anze Smole  3 ,  Daniel J Powell Jr  3  11 ,  Benjamin A Garcia  12 ,  Robert H Vonderheide  10  6  3  13 ,  Gerald P Linette  10  3  13 ,  Beatriz M Carreno  14  15  16
Affiliations
  • 1. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 2. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 3. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
  • 5. MSBioworks, Ann Arbor, MI, USA.
  • 6. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
  • 7. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 9. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
  • 10. Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 11. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12. Department of Biochemistry and Biophysics, Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 13. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 14. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 15. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 16. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
PMID: 34272369 DOI: 10.1038/s41467-021-24562-2
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.

Products