Estradiol initiates the immune escape of non-small cell lung cancer cells via ERβ/SIRT1/FOXO3a/PD-L1 axis.

Mounting evidence has postulated estrogen as a contributor for lung cancer development and progression. Here, we focused on the effect of estradiol (E2) on the immune escape of non-small cell lung cancer (NSCLC). The expression of FOXO3a in NSCLC samples was screened by gene microarray and then verified using Western blot analysis in NSCLC cell lines. Interaction between E2, SIRT1, FOXO3a and PD-L1 was determined. Following ectopic expression and depletion experiments in A549 and H1435 cells, cell proliferation and killing of cytotoxic T lymphocytes (CTLs) on NSCLC cells were evaluated. Xenograft mouse models were prepared to validate the in vivo effect of E2. E2 activated SIRT1 by up-regulating the expression of ERβ and thereby weakened the killing of CTLs on NSCLC cells. E2 elevated PD-L1 by up-regulating the ERβ/SIRT1 axis to promote the immune escape of NSCLC cells. SIRT1 degraded FOXO3a by reducing the acetylation level of FOXO3a and increased its ubiquitination. E2 inhibited the expression of FOXO3a and elevated PD-L1 expression, thereby promoting the immune escape of NSCLC cells. In vivo results showed that E2 facilitated the growth and metastasis of NSCLC cells in nude mice by elevating ERβ via SIRT1/FOXO3a/PD-L1 axis. In summary, our data revealed the critical roles of E2/ERβ/SIRT1/FOXO3a/PD-L1 axis in the immune escape of NSCLC cells and suggested that the axis may be promising therapeutic targets for NSCLC.