2022 Fiscal Year Final Research Report

Perspective of targeting cancer-associated fibroblasts in non-small-cell lung cancer

Research Project

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Project/Area Number	19H03745
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 55040:Respiratory surgery-related
Research Institution	Osaka University
Principal Investigator	Shintani Yasushi 大阪大学, 大学院医学系研究科, 教授 (90572983)
Co-Investigator(Kenkyū-buntansha)	大瀬尚子大阪大学, 大学院医学系研究科, 助教 (10570559) 舟木壮一郎大阪大学, 大学院医学系研究科, 准教授 (50464251) 狩野孝大阪大学, 大学院医学系研究科, 助教 (70528455) 南正人大阪大学, 医学部附属病院, 特任教授(常勤) (10240847)
Project Period (FY)	2019-04-01 – 2023-03-31
Keywords	肺癌 / 癌周囲微小環境 / 腫瘍免疫 / 癌関連線維芽細胞 / 上皮間葉移行
Outline of Final Research Achievements	In the tumor microenvironment of non-small cell lung cancer (NSCLC), cancer-associated fibroblasts (CAFs) interact with lung cancer cells via the TGF-β-IL-6 axis to control epithelial-mesenchymal transition (EMT), resulting in acquisition of malignancy and treatment resistance. CAFs regulated the cytotoxic activity of immune cells, creating a microenvironment of immune tolerance. We also showed that antifibrotic drugs or antibody therapy aimed at CAFs could be as a new lung cancer treatment. As we focused on several roles of CAFs in NSCLC tumorigenesis, owing to their heterogeneity, molecular markers of CAFs were elucidated to better classify tumor-promoting subtypes and facilitate the establishment of CAF-specific targeted therapies. Results thus far obtained have shown that CAF-targeted cancer treatment can suppress EMT, and also regulate the niche of cancer stem cells and the immunosuppressive network, thus may be found useful for cancer treatment through multiple mechanisms.
Free Research Field	呼吸器外科
Academic Significance and Societal Importance of the Research Achievements	近年、癌周囲微小環境を構築する細胞が癌の進展を多面的に促進させることが実証されつつあり、本研究によって癌関連線維芽細胞CAFを標的とした肺癌治療の有用性が示された。癌周囲微小環境内の免疫状態の解析から、抗腫瘍免疫に対するCAFを中心とした癌周囲微小環境内の意義を明らかにできる可能性が示唆された。遺伝子異常の頻度が高く薬剤耐性を生じやすい癌細胞に比較して、CAFを標的とした治療は抵抗性を生じにくいと予測され、既存の癌治療に相乗効果を見込め、CAFを標的とした治療を組み合わせることで治療耐性化を阻害でき、効果増強による投与量の減量、副作用の減少、投与期間短縮につながる可能性がある。