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

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Abstract

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.

About the authors

V. 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. V Zinovyeva

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences

Moscow, Russia

D. A Didych

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences

Moscow, Russia

I. V 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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