Elucidation of anti-tumor immune response through qualitative evaluation of neoantigens

• Project/Area Number: 21K20859
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Chiba University
• Principal Investigator: ISHINO Takamasa 千葉大学, 大学院医学研究院, 特任研究員 (90907792)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腫瘍免疫 / 免疫チェックポイント阻害剤 / ネオ抗原 / 大腸癌 / 大腸がん / MSI-high大腸癌

Outline of Research at the Start

免疫チェックポイント阻害剤は腫瘍のエフェクターT細胞（Teff）を活性化し効果を発揮するが、特に体細胞変異由来のネオ抗原を認識しているTeffが重要とされている。私達は体細胞変異数が非常に多い高頻度マイクロサテライト不安定性を有する大腸癌でネオ抗原に着目し、従来ネオ抗原はinflamedな腫瘍微小環境を誘導するとされてきたが、特定のネオ抗原では遺伝子変異が機能的にnoninflamedな腫瘍微小環境に誘導している可能性が示唆された。そこで、本研究では体細胞変異を量だけでなく質的にも評価して腫瘍微小環境への影響を解明し、抗腫瘍免疫応答の本態解明、より効果の高い治療や正確なバイオマーカーを目指す。

Outline of Final Research Achievements

We identified a shared neoantigen derived from a loss-of-function frameshift mutation in RNF43 through analysis of 88 colorectal cancers. However, patients with the mutated RNF43 did not have inflamed tumor microenvironment (TME). We revealed that loss of RNF43 function could paradoxically induce a non-inflamed TME leading to suppression of anti-tumor immunity. In addition, we demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types.
Our research propose the need to assess the qualities as well as the quantities of neoantigenic gene mutations, particularly driver gene mutations, as predictive biomarkers for ICI response.

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害剤は様々な癌腫で有効性が示され、化学療法の在り方を大きく変えたものの、その奏効率は未だ満足のいくものではなく、効果予測のバイオマーカーや耐性機序の解明が必要である。本研究では、これまでの体細胞変異数の量的な評価だけでは抗腫瘍免疫応答の予測は不十分で、遺伝子自体の機能といった質的な部分まで踏み込んだ解析の必要性を新たに提唱した点に意義があると考える。

Research Products

• [Journal Article] Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens (2023)
  • Author(s): Ishino Takamasa、Kawashima Shusuke、Tanji Etsuko、Ueno Toshihide、Ueda Youki、Ogasawara Sadahisa、Sato Kazuhito、Mano Hiroyuki、Ishihara Soichiro、Kato Naoya、Kawazu Masahito、Togashi Yosuke
  • Journal Title: British Journal of Cancer Volume: 128 Issue: 6 Pages: 1166-1175
  • DOI: 10.1038/s41416-023-02165-6
  • Peer Reviewed / Open Access
• [Journal Article] Activated CTLA‐4‐independent immunosuppression of Treg cells disturbs CTLA‐4 blockade‐mediated antitumor immunity (2023)
  • Author(s): Watanabe T、Ishino T、Ueda Y、Nagasaki J、Sadahira T、Dansako H、Araki M、Togashi Y
  • Journal Title: Cancer Science Volume: In press Issue: 5 Pages: 1859-1870
  • DOI: 10.1111/cas.15756
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of resistance to immune checkpoint inhibitors (2022)
  • Author(s): Nagasaki J、Ishino T、Togashi Y
  • Journal Title: Cancer Science Volume: 113 Issue: 10 Pages: 3303-3312
  • DOI: 10.1111/cas.15497
  • Peer Reviewed / Open Access
• [Presentation] Paradoxical neoantigens; neoantigenic mutations can paradoxically induce a noninflamed tumor microenvironment via their original functions (2022)
  • Author(s): Takamasa Ishino, Toshihide Ueno, Youki Ueda, Hiroyuki Mano, Soichiro Ishihara, Naoya Kato, Masahito Kawazu, Yosuke Togashi
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Neoantigen paradox; neoantigen do not always induce an inflamed tumor microenvironment (2022)
  • Author(s): Takamasa Ishino, Shusuke Kawashima, Etsuko Tanji, Toshihide Ueno, Youki Ueda, Sadahisa Ogasawara, Kazuhito Sato, Soichiro Ishihara, Naoya Kato, Masahito Kawazu, Yosuke Togashi
  • Organizer: 第12回日米癌合同会議