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Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice

BACKGROUND & AIMS: Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect recently has gained attention as a cancer immune-resistance mechanism....

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Detalles Bibliográficos
Autores principales: Sasaki, Kyo, Nishina, Sohji, Yamauchi, Akira, Fukuda, Kotaro, Hara, Yuichi, Yamamura, Masahiro, Egashira, Kensuke, Hino, Keisuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841526/
https://www.ncbi.nlm.nih.gov/pubmed/33191170
http://dx.doi.org/10.1016/j.jcmgh.2020.10.010
Descripción
Sumario:BACKGROUND & AIMS: Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect recently has gained attention as a cancer immune-resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against hepatocellular carcinoma in mice. METHODS: The antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models. RESULTS: The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T-cell trafficking. In addition, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-γ–positive T cells in liver tumors. Human CD8(+) T cells cocultured with 2DG-PLGA-NP–treated Huh7 cells showed their increased interferon-γ production and glucose uptake compared with the CD8(+) T cells co-cultured with PLGA-NP–treated Huh7 cells. Chemotaxis of CD8(+) T cells was suppressed by lactate and enhanced by glucose. Interferon-γ enhanced CD8(+) T-cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/CXCL10) production in liver tumors via interferon-γ–Janus kinase–signal transducers and activator of transcription pathway and 5' adenosine monophosphate-activated protein kinase–mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti–programmed death-1 antibody, but also suppressed anti–programmed death-1–resistant tumors. CONCLUSIONS: The newly developed 2DG-PLGA-NPs showed antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications.