A Study of the Effect of Lenvatinib on the Immune Microenvironment of Hepatocellular Carcinoma

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16332
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Hiroshima University
• Principal Investigator: Atsushi Ono 広島大学, 医系科学研究科(医), 助教 (80774645)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 肝細胞癌 / レンバチニブ / 腫瘍免疫微小環境

Outline of Final Research Achievements

Lenvatinib (LEN) plus anti-PD-L1 antibody, LEN alone, anti-PD-L1 antibody alone, or Vehicle was administered to an orthotopic transplanted mouse model of liver cancer.
Fluorescence-activated cell sorting revealed that tumor-infiltrating CD8-positive T cell (CTL) were highest in the combination group. On the other hand, there was no decrease in tumor-associated macrophages (TAM), as previously reported. The decrease of tumor-associated macrophages (TAM), previously reported, was not observed in this study. Therefore, we profiled the expression of immune related genes in human tumor biopsy specimens before and after LEN administration by nCounter and revealed that infiltration of CTLs were increased but TAMs were increased in human specimens as well. And also we revealed that serum IL8 and Ang2 was significantly decreased after the initiation of LEN treatment, which were considered to be a key immune activating mechanisms of LEN.

Free Research Field

肝臓病

Academic Significance and Societal Importance of the Research Achievements

レンバチニブ（LEN）は、肝細胞癌のがん免疫微小環境を、免疫チェックポイント阻害剤が奏効しやすい状態に誘導すると期待されているが、その機序については不明なことが多い。これまで腫瘍随伴マクロファージ（TAM）の減少がその機序の一つとして提唱されていたが、本研究結果は、TAMの現象以外に重要な免疫調整メカニズムが存在することを示唆するものと考える。その機序として、IL8や、Ang2-Tie2 axisの抑制が考えられた。現在、in vivoでの機能解析を進めているところであるが、これらの結果は、LENと免疫チェックポイント阻害剤との併用の妥当性を示す結果と考察される。