Details

Autor(en) / Beteiligte

• Watanabe, Shunichi
• Takagi, Ayaka
• Yuba, Eiji
• Kojima, Chie
• Dei, Nanako
• Matsumoto, Akikazu
• Tanikawa, Jun
• Kawamura, Tetsuya
• De Silva, Nadeeka H.
• Izawa, Takeshi
• Akazawa, Takashi
• Kanegi, Ryoji
• Hatoya, Shingo
• Inaba, Toshio
• Sugiura, Kikuya

Titel

In vivo transfection of cytokine genes into tumor cells using a synthetic vehicle promotes antitumor immune responses in a visceral tumor model

Ist Teil von

• The FASEB journal, 2023-11, Vol.37 (11), p.e23228-n/a

Erscheinungsjahr

2023

Quelle

Access via Wiley Online Library

Beschreibungen/Notizen

• The tumor microenvironment (TME) strongly affects the clinical outcomes of immunotherapy. This study aimed to activate the antitumor immune response by manipulating the TME by transfecting genes encoding relevant cytokines into tumor cells using a synthetic vehicle, which is designed to target tumor cells and promote the expression of transfected genes. Lung tumors were formed by injecting CT26.WT intravenously into BALB/c mice. Upon intravenous injection of the green fluorescent protein‐coding plasmid encapsulated in the vehicle, 14.2% tumor‐specific expression was observed. Transfection of the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and CD40 ligand (L)‐plasmid combination and interferon gamma (IFNγ) and CD40L‐plasmid combination showed 45.5% and 54.5% complete remission (CR), respectively, on day 60; alternate treatments with both the plasmid combinations elicited 66.7% CR, while the control animals died within 48 days. Immune status analysis revealed that the density of dendritic cells significantly increased in tumors, particularly after GM‐CSF‐ and CD40L‐gene transfection, while that of regulatory T cells significantly decreased. The proportion of activated killer cells and antitumoral macrophages significantly increased, specifically after IFNγ and CD40L transfection. Furthermore, the level of the immune escape molecule programmed death ligand‐1 decreased in tumors after transfecting these cytokine genes. As a result, tumor cell‐specific transfection of these cytokine genes by the synthetic vehicle significantly promotes antitumor immune responses in the TME, a key aim for visceral tumor therapy. Tumor‐specific transfection and efficient expression of genes encoding GM‐CSF, CD40L, and IFNγ can be achieved using synthetic vehicles. Expressed cytokines induce the production of DCs from monocytes and their maturation, convert the microphage population from M2 to M1, activate natural killer (NK) and cytotoxic T lymphocyte (CTL) generated by the interaction of T cells with mature DC, and suppress the immune escaping molecule, PDL‐1 expression. These changes enhance tumor immunity in the microenvironment and significantly elicit therapeutic effects.