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Cancer Immunol Res. 2016 Dec;4(12):1007-1015. Epub 2016 Oct 31.

Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach.

Author information

1
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
2
Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri.
3
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
4
The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri.
5
The McDonnell Genome Institute, Washington University, St. Louis, Missouri.
6
Division of Genomics and Bioinformatics, Department of Medicine, Washington University, St. Louis, Missouri.
7
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
8
Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri. gpdunn@wustl.edu.

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-2Kb and H-2Db candidate 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 Imp3D81N and Odc1Q129L were 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.

PMID:
27799140
PMCID:
PMC5215735
DOI:
10.1158/2326-6066.CIR-16-0156
[Indexed for MEDLINE]
Free PMC Article

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