Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer

An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with ⁶⁴Cu-trastuzumab (⁶⁴Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced ⁶⁴Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using ⁶⁴Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.