OA03-RF01.11. Elucidation of the Function of Proline Isomerase Pin1 on Esophageal Squamous Cell Carcinoma

Abstract

Abstract Topic Esophageal Cancer: Molecular Biology/Pathology Background Esophageal squamous cell carcinoma (ESCC) shows limited response to anti-PD-1 monotherapy, prompting interest in combination treatments. Pin1, highly expressed in ESCC and other cancers, drives malignancy. Studies indicate that Pin1 inhibition elevates PD-L1 and enhances anti-PD-1 efficacy. This study explores the effects of Pin1 inhibition in ESCC. Methods In this study, all-trans retinoic acid and arsenic trioxide (ATRA+ATO), which are Pin1 inhibitors, were added to the ESCC cell lines KYSE410 and TE8. Survival rates, migration ability, and protein expression were analyzed 72 hours after compound addition. Protein expression was analyzed by Western blotting targeting Pin1, E-cadherin, NF-κB, and PD-L1, with β-actin as a control.Furthermore, Pin1 knockdown was performed in KYSE410 cells, and Pin1 and PD-L1 expression was examined by qRT-PCR and Western blotting. Clinical specimens were pre-treatment biopsy samples from ESCC patients who received anti-PD-1 antibody therapy after chemoradiotherapy and were treated at the Esophageal and Gastrointestinal Surgery Department of the same hospital. This study evaluated the Pin1 immunohistochemical staining pattern and the response to anti-PD-1 antibody therapy. Results In the KYSE410 and TE8 cells, the combination of ATRA and ATO was found to reduce survival rates and decrease the number of migratory cells, depending on the concentration used. With regard to protein expression, Pin1 and NF-κB were reduced in comparison with untreated cells, whilst E-cadherin and PD-L1 increased. The knockdown of Pin1 resulted in a reduction of both Pin1 mRNA and protein levels in comparison with the negative control, whilst PD-L1 mRNA exhibited no consistent change, with PD-L1 protein levels increasing. A detailed analysis of biopsy specimens was conducted, revealing that cases exhibiting elevated Pin1 expression demonstrated a tendency to exhibit a diminished response to anti-PD-1 antibody therapy. Conclusion Pin1 inhibition by ATRA + ATO is suggested to contribute to cell proliferation suppression via NF-κB reduction and to inhibition of epithelial-mesenchymal transition through increased E-cadherin. Furthermore, based on PD-L1 increase due to Pin1 reduction and results from biopsy specimens, Pin1 inhibition may reduce tumor malignancy while enhancing treatment responsiveness to anti-PD-1 antibody therapy. Furthermore, results from Pin1 knockdown suggest that Pin1 reduction does not regulate PD-L1 mRNA expression but rather inhibits PD-L1 protein degradation. Collectively, these findings suggest that combining anti-PD-1 therapy with Pin1 inhibition may be effective.