title: Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach.
abstract: The "cancer immunogenomics" paradigm has facilitated the search for tumor-specific antigens over the last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific "neoantigens" in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. GL261 and SMA-560 harbored 4,932 and 2,171 nonsynonymous exome mutations, respectively, of which less than half were expressed. To establish the immunogenicities of H-2Kband H-2Dbcandidate neoantigens, we assessed the ability of the epitopes predicted in silico to be the highest affinity binders to activate tumor-infiltrating T cells harvested from GL261 and SMA-560 tumors. Using IFNγ ELISPOT, we confirmed H-2Db-restricted Imp3D81N(GL261) and Odc1Q129L(SMA-560) along with H-2Kb-restricted E2f8K272R(SMA-560) as endogenous tumor-specific neoantigens that are functionally immunogenic. Furthermore, neoantigen-specific T cells to Imp3D81Nand Odc1Q129Lwere detected within intracranial tumors as well as cervical draining lymph nodes by tetramer analysis. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell-activating immunotherapeutic approaches in preclinical models of glioblastoma. Cancer Immunol Res; 4(12); 1007-15. ©2016 AACR.
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.
authors: Tanner M
authors: TM
authors: Johanns
authors: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.|Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.|The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
authors: Jeffrey P
authors: JP
authors: Ward
authors: The McDonnell Genome Institute, Washington University, St. Louis, Missouri.|Division of Genomics and Bioinformatics, Department of Medicine, Washington University, St. Louis, Missouri.
authors: Christopher A
authors: CA
authors: Miller
authors: Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors: Courtney
authors: C
authors: Wilson
authors: Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.|Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors: Dale K
authors: DK
authors: Kobayashi
authors: Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.
authors: Diane
authors: D
authors: Bender
authors: Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.|Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors: Yujie
authors: Y
authors: Fu
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors: Anton
authors: A
authors: Alexandrov
authors: The McDonnell Genome Institute, Washington University, St. Louis, Missouri.|Division of Genomics and Bioinformatics, Department of Medicine, Washington University, St. Louis, Missouri.
authors: Elaine R
authors: ER
authors: Mardis
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors: Maxim N
authors: MN
authors: Artyomov
authors: Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.|The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
authors: Robert D
authors: RD
authors: Schreiber
authors: Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri. gpdunn@wustl.edu.|Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.|The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
authors: Gavin P
authors: GP
authors: Dunn
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D059472:Exome; D005805:Genes, MHC Class I; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics* / Q000276:immunology*; D008810:Mice, Inbred C57BL; D017423:Sequence Analysis, RNA
chemical_list: D000951:Antigens, Neoplasm