Prediction of immunogenic neoantigens based on pHLA structure

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K21528
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Sapporo Medical University
• Principal Investigator: KANASEKI Takayuki 札幌医科大学, 医学部, 講師 (50531266)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: 腫瘍免疫 / 腫瘍抗原 / ネオアンチゲン / HLA / CD8 T細胞

Outline of Final Research Achievements

CD8 T cells recognize neoantigens that arise from somatic mutations, discriminating cancer cells. However, the nature of neoantigens that confer immunogenicity on wild-type peptides remains unclear. Here, we conducted proteogenomic HLA ligandome analysis and identified a series of neoantigens naturally displayed by a human colon cancer line. We found that the antigenicity to induce healthy donor-derived CD8 T cells varies among the identified neoantigens. Further, we prepared a panel of neoantigen variants that differed in substituted amino acids, and assessed their antigenicity. As a result, we found that the antigenicity was positively associated with the difference between the neoantigen variants and wild-type peptides in their pHLA 3D structure. Delta ASA (accessible surface are of pHLAs between neoantigen and wild type) scores based on 3D structure may benefit immunogenicity prediction of neoantigens.

Free Research Field

腫瘍免疫

Academic Significance and Societal Importance of the Research Achievements

腫瘍の体細胞遺伝子変異量（TMB）は免疫チェックポイント阻害剤の効果バイオマーカーである。しかし、多くのがん種類で奏効率は20%程度にとどまっている。今回、免疫応答を惹起する変異を予測する新しい方法を開発できた。pHLAの立体構造差に基づくアルゴリズムである。つまり、従来バイオマーカーである変異「量」に変異の「質」的評価を上乗せすることが出来る。本法は新しい免疫チェックポイントバイオマーカーとして役立つ可能性があり、免疫チェックポイント阻害剤患者コホートを用いた検証を検討している。臨床応用による社会貢献を目指す。