Tinagl1 gene therapy suppresses growth and remodels the microenvironment of triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat and is responsible for approximately 12% of breast cancer cases in the US per year. In 2019, the protein Tinagl1 was identified as a key factor for improved prognoses in certain TNBC patients. While the intracellular mechanism of action has been thoroughly studied, little is known about the role of Tinagl1 in the tumor microenvironment. In this study, we developed a lipid nanoparticle-based gene therapy to directly target the expression of Tinagl1 in tumor cells for localized expression. Additionally, we sought to characterize the changes to the tumor microenvironment induced by Tinagl1 treatment, with the goal of informing future choices for combination therapies including Tinagl1. We found that Tinagl1 gene therapy was able to slow tumor growth from the first dose and that the effects held steady for nearly a week following the final dose. No toxicity was found with this treatment. Additionally, the use of Tinagl1 increases the tumor vasculature by 3-fold but does not increase the tumor permeability or risk of metastasis. However, the increase in vasculature arising from Tinagl1 therapy reduced the expression of Hif1a significantly (p < 0.01), which may decrease the risk of drug resistance.