Endogenous neoantigen-specific CD8 T cells identified in two glioblastoma models using a cancer immunogenomics approach

Tanner M. Johanns, Jeffrey P. Ward, Christopher A. Miller, Courtney Wilson, Dale K. Kobayashi, Diane Bender, Yujie Fu, Anton Alexandrov, Elaine R. Mardis, Maxim N. Artyomov, Robert D. Schreiber, Gavin P. Dunn

Research output: Contribution to journalArticle

33 Scopus citations

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 IFNγg 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.

Original languageEnglish
Pages (from-to)1007-1015
Number of pages9
JournalCancer immunology research
Volume4
Issue number12
DOIs
StatePublished - Dec 2016

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