Gene electrotransfer of proinflammatory chemokines CCL5 and CCL17 as a novel approach of modifying cytokine expression profile in the tumor microenvironment

• Published in: Bioelectrochemistry (Amsterdam, Netherlands) Netherlands), 2021-08, Vol.140, p.107795-107795, Article 107795
• Main Authors: Bozic, T., Sersa, G., Kranjc Brezar, S., Cemazar, M., Markelc, B.
• Format: Article
• Language: English
• Subjects: Animal models; Breast cancer; CCL17; CCL17 protein; CCL5; Chemokines; Colon; Cytokine expression; Cytokines; Cytosol; Deoxyribonucleic acid; DNA; Electroporation; Gene electrotransfer; Gene expression; Gene therapy; Gene transfer; Immune system; Immunotherapy; Inflammation; Murine tumors; Plasmids; Schedules; Transgenes; Tumor microenvironment; Tumors; γ-Interferon
• ISSN: 1567-5394; 1878-562X
• DOI: 10.1016/j.bioelechem.2021.107795

•In vitro, lipofection of CCL5/CCL17 modifies the expression of cytokines.•The main driver of these changes was the entry of foreign DNA into the cytosol.•In vivo, ECT pulses lead to high expression of Ccl5 and Ccl17 after GET.•GET of CCL5 or CCL17 results in increased expression of Cxcl9 and Ifnγ.•Cxcl9 and Ifnγ are potent activators of the immune system in the CT26 tumor model. The effectiveness of immunotherapy highly correlates with the degree and the type of infiltrated immune cells in the tumor tissue. Treatments based on modifying the immune cell infiltrate of the tumor microenvironment are thus gaining momentum. Therefore, the aim of our study was to investigate the effects of gene therapy with two proinflammatory chemokines CCL5 and CCL17 on inflammatory cytokine expression profile and immune cell infiltrate in two murine breast tumor models, 4T1 and E0771, and two murine colon tumor models, CT26 and MC38. In vitro, lipofection of plasmid DNA encoding CCL5 or CCL17 resulted in changes in the cytokine expression profile similar to control plasmid DNA, implying that the main driver of these changes was the entry of foreign DNA into the cell’s cytosol. In vivo, gene electrotransfer resulted in high expression levels of both Ccl5 and Ccl17 transgenes in the 4T1 and CT26 tumor models. Besides a minor increase in the survival of the treated mice, the therapy also resulted in increased expression of Cxcl9 and Ifnγ, potent activators of the immune system, in CT26 tumors. However, this was not recapitulated in changes of TME, implying that a further refinement of the dosing schedule is needed.