Exploring Novel Cancer Immunotherapy to Turn Cold Tumors into Hot Tumors by RNA Editing

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17653
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Okayama University
• Principal Investigator: Shigeyasu Kunitoshi 岡山大学, 大学病院, 助教 (70544071)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: RNA編集 / ネオアンチゲン / 大腸癌 / 直腸癌 / 化学放射線療法 / ADAR1 / オキサリプラチン

Outline of Final Research Achievements

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate.

Free Research Field

Epigenetics

Academic Significance and Societal Importance of the Research Achievements

本研究は、CRTによるRNA編集を用いてエピジェネティックな多様性を制御する方法についての新しい証拠を提供するものである。本研究は、CRC患者、特に局所進行直腸癌における免疫療法のためのRNA編集の生物学的および臨床的意義を強調するものである。我々の知見は、OXを用いたCRTがICIに対する免疫反応性を促進する効果的な治療法であることを示唆している。特に、この技術は直腸癌患者におけるwatch and wait療法として有用であろう。