Development of Innovative Hepatocellular Carcinoma Therapies Targeting Cancer Metabolism and Tumor Immunity Regulated by MYC and PGC1a

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15545
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kumamoto University
• Principal Investigator: Kitano Yuki 熊本大学, 病院, 特任助教 (40814760)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 肝細胞癌 / がん代謝 / 腫瘍免疫

Outline of Final Research Achievements

This study aims to elucidate the impact of "cancer metabolism" regulated by MYC and PGC1a on "tumor immunity" and mechanisms involved in cancer progression in hepatocellular carcinoma (HCC).
Analysis of TCGA datasets revealed that in HCC, the high expression of MYC (HR=1.75, P=0.008) and the low expression group of PGC1a (HR=2.33, P<0.0001) had a worse prognosis. A signature combining the expression levels of cancer metabolism-related genes including MYC and PGC1a revealed enhanced glycolysis in poorly differentiated HCC. In 225 resected specimens of HCC, the expression of immune cells was examined within the tumor and at its periphery. At the tumor periphery, the low expression of CD8+ T cells and the high expression of tumor-infiltrating neutrophils and macrophages were significantly associated with poorer prognosis. Assessment of the tumor immune environment using immune cells revealed that cold tumors were significantly associated with worse prognosis compared to hot tumors.

Free Research Field

肝胆膵外科

Academic Significance and Societal Importance of the Research Achievements

本研究では、肝細胞癌においてMYC, PGC1αらに制御される“がん代謝”が“腫瘍免疫”に与える影響と、癌の進展に関与するメカニズム解明を目的とした。
がん代謝制御因子であるMYCとPGC1αの発現レベルが肝細胞癌患者の生命予後に関与し、さらに悪性度の高い低分化肝細胞癌でがん代謝が亢進していることが分かった。さらに肝細胞癌腫瘍周辺の腫瘍免疫環境（hot/cold tumor）も予後に関与することが分かった。これらの結果より、肝細胞癌においてがん代謝と腫瘍免疫は非常に重要な役割を果たしており、MYCとPGC1αは治療標的となり得ることを示した。