Improved Efficiency of OX40L-Based Gene Therapy Using a Non-Viral Delivery System in Fibroblast-Enriched Mouse Tumor Models

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Malignant tumors, during their progression, are capable of forming a permissive microenvironment that influences their further growth and development. Tumor-associated fibroblasts (TAFs) play a significant role in this process. In the present study, we generated subcutaneous murine tumors by inoculating a co-culture of cancer cells and fibroblasts to create tumors enriched with microenvironmental cells. Once the tumor nodule had formed, an intratumoral injection was performed using a formulation containing a plasmid encoding the ligand for immune checkpoint receptors –OX40L – under the control of a CMV promoter. For efficient cellular delivery, the plasmid was encapsulated in a polymer shell based on PEG-PEI-TAT. We evaluated the impact of this treatment on tumor growth. In this experimental model, fibroblasts were artificially introduced into the tumor to partially simulate a developed tumor microenvironment. These tumors demonstrated an increased proliferation rate. However, intratumoral administration of the non-viral OX40L-encoding agent into fibroblast-enriched tumors resulted in a notable increase in the rate of complete tumor regression, reaching up to 25%. It is hypothesized that introduced fibroblasts may perform antigen-presenting functions and/or serve as an additional source of signals that activate the immune system.

作者简介

V. Pleshkan

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences; KC NBICS-nature-like technologies, NRC "Kurchatov Institute"

Email: vpleshkan@gmail.com
Moscow, Russia; Moscow, Russia

M. Zinovyeva

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences

Moscow, Russia

D. Didych

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences

Moscow, Russia

I. Alekseenko

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences; KC NBICS-nature-like technologies, NRC "Kurchatov Institute"

Moscow, Russia; Moscow, Russia

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