119P The role and mechanism of estrogen receptor beta based on SRSF2 in gender differences of lung adenocarcinoma immunotherapy with anti-PD-1

The progression free survival (PFS) of male lung cancer patients is significantly higher than that of females after receiving anti PD-1/PD-L1 treatment, this study aims to explore the role and mechanism of estrogen in anti PD-1/PD-L1 immunotherapy for lung adenocarcinoma. Exploring the expression levels and correlation of ERβ/SRSF2/PD-L1 and their relationship with the prognosis of lung adenocarcinoma patients based on the tissue chips of 159 lung adenocarcinoma patients with complete follow-up data in Zhongnan Hospital of Wuhan University and 515 lung adenocarcinoma patients of TCGA database. Knockdown or overexpression of ERβ/SRSF2 in H1299 cell line, combined with Western blot, qPCR, Co-IP, and RIP to verify the correlation between the three molecules, exploring the cytological effects of tumors with its different expression levels. A subcutaneous lung cancer model was established in C57/BL mice by LLC cells, treated with anti PD-1 therapy (Pembrolizumab), recording the growth curves of different groups of tumors and measuring the final tumor volume and mass. IHC, WB, qPCR, and flow cytometry were used to further verify the mechanism of ERβ based on SRSF2 in gender differences of lung adenocarcinoma immunotherapy with anti-PD-1. The tissue chip immunohistochemistry staining and TCGA database both display that there is a significant correlation (P<0.05) between ERβ, SRSF2 and PD-L1, and high ERβ or PD-L1 is associated with poor prognosis in lung adenocarcinoma patients (P<0.05). The three molecules are positively correlated. E2 and ERβ mediating the upregulation of PD-L1 expression by SRSF2 and enhancing the proliferation, migration, and invasion of H1299 cells, while knocking down SRSF2 or Fulvestrant has the opposite effect. E2 can promote the growth of lung adenocarcinoma in mice. After treatment with pembrolizumab, male mice have a longer PFS, but female mice are more likely to benefit from it. E2 also has a significant impact on the tumor microenvironment of mice. E2 and ERβ regulating SRSF2 and upregulating PD-L1 expression may be a mechanism for gender differences in the efficacy of anti-PD-1/PD-L1 immunotherapy in lung adenocarcinoma patients.