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

• Published in: Cancer immunology research Vol. 4; no. 12; p. 1007
• Main Authors: Johanns, Tanner M, Ward, Jeffrey P, Miller, Christopher A, Wilson, Courtney, Kobayashi, Dale K, Bender, Diane, Fu, Yujie, Alexandrov, Anton, Mardis, Elaine R, Artyomov, Maxim N, Schreiber, Robert D, Dunn, Gavin P
• Format: Journal Article
• Language: English
• Published: United States 01-12-2016
• Subjects: Animals; Antigens, Neoplasm - immunology; Brain Neoplasms - genetics; Brain Neoplasms - immunology; CD8-Positive T-Lymphocytes - immunology; Disease Models, Animal; Exome; Genes, MHC Class I; Genomics; Glioblastoma - genetics; Glioblastoma - immunology; Mice, Inbred C57BL; Sequence Analysis, RNA
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-16-0156

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-2K
and H-2D
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-2D
-restricted Imp3
(GL261) and Odc1
(SMA-560) along with H-2K
-restricted E2f8
(SMA-560) as endogenous tumor-specific neoantigens that are functionally immunogenic. Furthermore, neoantigen-specific T cells to Imp3
and Odc1
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. ©2016 AACR.