HLA presentation mechanisms of long non-coding RNA-derived cancer antigens

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03490
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: KANASEKI Takayuki 札幌医科大学, 医学部, 講師 (50531266)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 腫瘍免疫 / 抗原 / HLA / T細胞 / 免疫治療 / ノンコーディングRNA

Outline of Final Research Achievements

We developed proteogenomic HLA ligandome analysis employing mass spectrometry and RNA-seq, and found that cryptic peptides, which were not registered in the present proteome databases, accounted for approximately 5% of the immunopeptidome of human colon cancer tissues. We identified a peptide that originated from the oncogenic long non-coding RNA (lncRNA), PVT1. The PVT1 peptide was enriched in cancer tissues compared with normal mucosa, and was immunogenic to induce specific T cell responses in both patients and healthy donors. Interestingly, the peptide was encoded by a short ORF, which was followed by a premature termination codon. We found that the inhibition of nonsense mediated RNA decay (NMD) enhanced T cell responses to cancer cells that endogenously expressed the PVT1 gene. These results indicate the presence of a novel class of tumor antigens encoded by lncRNAs, and demonstrate a potential mechanism that regulate their antigen presentation.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

T細胞はHLA提示された抗原ペプチドを認識し、腫瘍を拒絶する。抗原ペプチドはT細胞反応を導くカギの役割を果たす。既存の免疫チェックポイント阻害剤はどれも対象腫瘍のMHC提示ペプチド配列を考慮しない治療法である。しかし、適切な抗原配列を取得し標的として治療に組み込むことができれば、免疫治療効果の改善・上乗せを期待できる。本研究では世界に先駆けてlncRNAにコードされる新しいがん抗原クラスを発見し、その抗原提示メカニズムを明らかにした。免疫治療の新しい標的として、標準治療の創出につながる発見と考える。