Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma.

Abstract

Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II-IV glioma patients (glioblastoma, IDH-wild-type, n = 8; grade II-III astrocytoma, IDH-mutant, n = 9; and grade II-III oligodendroglioma, IDH-mutant, 1p/19q-codeleted, n = 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the "neoantigen expression ratio," decreased significantly at recurrence (P = 0.003). This phenomenon was particularly pronounced for "high-affinity," "clonal," and "passenger gene-derived" neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.

• Authors: Takahide Nejo, Hirokazu Matsushita, Takahiro Karasaki, Masashi Nomura, Kuniaki Saito, Shota Tanaka, Shunsaku Takayanagi, Taijun Hana, Satoshi Takahashi, Yosuke Kitagawa, Tsukasa Koike, Yukari Kobayashi, Genta Nagae, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno, Yoshitaka Narita, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani, Akitake Mukasa, Nobuhito Saito, Kazuhiro Kakimi
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 7 Pg. 1148-1161 (07 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 31088845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor

Topics

• Adult
• Aged
• Antigens, Neoplasm (genetics, immunology)
• Biomarkers, Tumor (genetics, immunology)
• Brain Neoplasms (genetics, immunology, pathology, surgery)
• Exome
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Glioma (genetics, immunology, pathology, surgery)
• High-Throughput Nucleotide Sequencing
• Humans
• Immune Evasion (immunology)
• Longitudinal Studies
• Lymphocytes, Tumor-Infiltrating (immunology)
• Male
• Middle Aged
• Mutation
• Neoplasm Recurrence, Local (genetics, immunology, pathology, surgery)
• Prognosis
• Retrospective Studies
• Survival Rate
• Young Adult