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

2022 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

消化器内科学

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。