Development of an anticancer therapy against liver cancer using 2-deoxy-D-glucose encapsulated in polymer poly (lactic-co-glycolic acid) nanoparticles

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07923
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Nishina Sohji 川崎医科大学, 医学部, 准教授 (70550961)
• Co-Investigator(Kenkyū-buntansha): 原 裕一 川崎医科大学, 医学部, 講師 (60550952) ; 日野 啓輔 川崎医科大学, 医学部, 教授 (80228741)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: がん / 解糖系 / ドラッグデリバリー / ナノ粒子 / 腫瘍免疫

Outline of Final Research Achievements

The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T cell trafficking. Additionally, 2DG-PLGA-NPs induced decreased lactate production and increased IFNγ-positive T cells in liver tumors. Human CD8+ T cells cocultured with 2DG-PLGA-NP-treated Huh7 cells revealed their increased IFNγ production and glucose uptake compared to the CD8+ T cells cocultured with PLGA-NP-treated Huh7 cells. Chemotaxis of CD8+ T cells was suppressed by lactate and enhanced by glucose. IFNγ enhanced CD8+ T cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9-11) production in liver tumors via IFNγ/STAT pathway and AMPK-mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by anti-PD1 antibody but also suppressed anti-PD1-resistant tumors.

Free Research Field

肝臓学

Academic Significance and Societal Importance of the Research Achievements

がん研究において腫瘍免疫は最もactiveかつcompetitiveな分野のひとつである。また、がん代謝とがん微小環境における腫瘍免疫との関連についての研究も盛んに行われている。2DG-PLGA-NPによるがん特異的な糖代謝阻害作用は、現在実用化されている抗PD-1抗体等の免疫チェックポイント阻害剤とは異なる作用機序で腫瘍免疫を活性化する可能性があり、また肝細胞癌以外のがん治療に応用できる可能性がある。