@article{fb3eaef199484a7ab6a692864cb90cc1,
title = "Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting",
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.",
author = "Bear, {Adham S.} and Tatiana Blanchard and Joseph Cesare and Ford, {Michael J.} and Richman, {Lee P.} and Chong Xu and Baroja, {Miren L.} and Sarah McCuaig and Christina Costeas and Khatuna Gabunia and John Scholler and Posey, {Avery D.} and O{\textquoteright}Hara, {Mark H.} and Anze Smole and Powell, {Daniel J.} and Garcia, {Benjamin A.} and Vonderheide, {Robert H.} and Linette, {Gerald P.} and Carreno, {Beatriz M.}",
note = "Funding Information: R.H.V. reports having received consulting fees or honoraria from Medimmune and Ver-astem; and research funding from Fibrogen, Janssen, and Lilly. He is an inventor on a licensed patent relating to cancer cellular immunotherapy and cancer vaccines, and receives royalties from Children{\textquoteright}s Hospital Boston for a licensed research-only monoclonal antibody. A.S.B., R.H.V., G.P.L., and B.M.C. have filed a patent application (PCT/US2020/014988) related to the targeting of KRAS for immunotherapy entitled “Compositions and Methods for Targeting Mutant RAS”. A.S., A.D.P., and D.J.P. have filed a patent application (PCT/ US2019/026378) that incorporates discoveries related to the NFAT reporter system used in this study entitled “Methods and Compositions Comprising a Viral Vector for Expression of a Transgene and an Effector”. M.J.F. is a founder and an employee of MS Bioworks. All other authors have no competing interest to declare. Funding Information: We thank the Human Immunology Core at the Univerisity of Pennsylvania for providing leukocytes for research, Drs Nina Luning Prak and Wenzhao Meng for assistance in TCR sequencing, Drs Rico Buchli, Thomas Osterbye, and Anette Stryhn for assistance in biochemical characterization of peptide epitopes, Dr Andrew Rech for bioinformatic analysis, Bereket Gebregziabher and Dr Nune Markosyan for statistical analysis, and Drs Carl June and Elizabeth Jaffee for advice and helpful discussions. This work was supported by NIH R01 CA204261 (to B.M.C. and G.P.L.), NIH P30 CA016520 (to R.H.V.), NIH CA196539 and CA232568 (to B.A.G.), SU2C/Lustgarten Foundation Pancreatic Cancer Collective (to R.H.V. and B.M.C.), the Parker Institute for Cancer Immunotherapy (to B.M.C., G.P.L., and R.H.V.), and Institute for Immunology at University of Pennsylvania (to A.S.B. and G.P.L.). Training grants provided support to A.S.B. (K12 CA076931) and T.B. (T32 CA009140). Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-24562-2",
language = "English",
volume = "12",
journal = "Nature communications",
issn = "2041-1723",
number = "1",
}