Proposing regulatory mechanisms of innate immune system manipulated by cancer-derived extracellular vesicles

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K18248
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Osaka University
• Principal Investigator: Kazutake Tsujikawa 大阪大学, 大学院薬学研究科, 教授 (10207376)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: 大腸がん / 細胞外小胞 / RNA脱メチル化 / ALKBH5 / がん微小環境 / TLR8 / tRF / 自然免疫

Outline of Final Research Achievements

This study challenged the question of whether autologous cell-derived cancer cells can manipulate cellular functions of the innate immune system and, if so, by what mechanisms cancer cell survival and proliferation are promoted. We found that colon cancer cells encapsulate and release N6-methyladenosine-deleted RNA in extracellular vesicles. This RNA activated TLR8 in monocytes and macrophages, causing them to release the proinflammatory cytokines TNF-α and IL-6. These cytokines promoted cancer cell proliferation. These results provide evidence for the existence of a mechanism by which cancer cells alter the RNA modifier balance with normal cells, encapsulate and release them into the EV, and activate the innate immune system to induce a cancer cell-significant microenvironment.

Free Research Field

細胞生理学

Academic Significance and Societal Importance of the Research Achievements

本研究では、がん細胞が細胞外小胞にRNA、特にN6-メチルアデノシン修飾体バランスを変えたtRNA-derived fragment (tDR）を含有させて放出し、あえて単球やマクロファージのパターン認識受容体TLR8に非自己として認識させることにより自然免疫系を活性化させ、サイトカインTNF-alphaやIL-6の産生をがん細胞有意な微小環境へと誘導する戦略を取っている、というこれまでの学術体系の変革をもたらす研究成果を取得したものである。