%A Kang,Changhee %A Song,Chin-Hee %A Kim,Nayoung %A Nam,Ryoung Hee %A Choi,Soo In %A Yu,Jeong Eun %A Nho,Heewon %A Choi,Jin A. %A Kim,Jin Won %A Na,Hee Young %A Lee,Ha-Na %A Surh,Young-Joon %D 2021 %J Frontiers in Oncology %C %F %G English %K 17β-estradiol,Nrf2,programmed death-ligand 1,Inflammation,immune microenvironment %Q %R 10.3389/fonc.2021.679324 %W %L %M %P %7 %8 2021-July-08 %9 Original Research %+ Nayoung Kim,Departments of Internal Medicine, Seoul National University Bundang Hospital,Republic of Korea,nakim49@snu.ac.kr %+ Nayoung Kim,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine,Republic of Korea,nakim49@snu.ac.kr %# %! Estrogen ameliorates immune microenvironment %* %< %T The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer %U https://www.frontiersin.org/articles/10.3389/fonc.2021.679324 %V 11 %0 JOURNAL ARTICLE %@ 2234-943X %X Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a dual role in carcinogenesis. We previously reported that Nrf2 deficiency enhances the anti-tumorigenic effect of 17β-estradiol (E2) in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model of colitis-associated cancer (CAC). Herein, we aimed to determine a possible explanation for our recent work and investigated the immune microenvironment represented by programmed death-ligand 1 (PD-L1) expression. One week after the AOM injection, mice were administered with DSS in drinking water for seven days; daily E2 injections were intraperitoneally administered during this period. The mice were sacrificed 16 weeks after AOM injection and analyzed for PD-L1 expression in the distal colon tissues using Western blotting and immunohistochemistry (IHC). Based on Western blotting results, PD-L1 expression was reduced in Nrf2 knockout (KO) female and E2-treated male mice when compared with their wild-type counterparts, following AOM/DSS treatment; this supports the association of PD-L1 expression with tumor progression. Additionally, this finding was in good agreement with the IHC results for PD-L1. Furthermore, we observed that PD-L1 is predominantly expressed in stromal cells rather than on epithelial cells in the colon. Western blotting revealed that PD-L1 expression in the colon positively correlates with expressions of inducible nitric oxide synthase (iNOS) (male, P = 0.002; female, P <0.001) and cyclooxygenase-2 (COX-2) (male, P <0.001; female, P <0.001). Collectively, our findings indicate that estrogen ameliorates the immune microenvironment represented by PD-L1 expression and enhances its effect in the absence of Nrf2.