Abstract 5474: PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma

Abstract

Abstract PD-L1 has been known to play a major role in suppressing the immune system. The effect of PD-L1 has been clinically studied by inhibiting PD-L1 in tumor and tumor-infiltrating immune cells, thereby activating anti-tumor T cells and re-establishing anti-tumor immune responses. Little is known about a unique role of PD-L1 in cisplatin chemoresistance of head and neck squamous cell carcinoma (HNSCC). The aim of the current study is to investigate a novel finding that PD-L1 regulates DNA double strand break (DSB) repairs via the MRE11-RAD50-NBS1 (MRN) complex and contributes to cisplatin chemoresistance in HNSCC. Well-characterized HNSCC tumor cell lines were used for this study. JHU 006 tumor cell line has a cisplatin resistant phenotype whereas JHU 020 is cisplatin sensitive. PD-L1 expression was determined by quantitative polymerase chain reaction (qPCR) and western blot before and after cisplatin treatment. The interactions between PD-L1 and MRN in DNA DSB mediated chemoresistant pathway were studied. PD-L1 siRNA was used to induce chemosensitization of HNSCC cells to cisplatin. Our study demonstrates that treatment of HNSCC cells with cisplatin resulted in increased expression of PD-L1 in cisplatin resistant tumor cells, whereas chemosensitive tumor cells showed no change in PD-L1 expression. Additionally, knockdown of PD-L1 using siRNA resulted in downregulation of NBS1, a key protein of the MRN DNA DSB repair complex. However, NBS1 was able to modulate the levels of PD-L1 expression as the use of either NBS1 siRNA or cells that had been transfected with a dominant negative NBS1 mutant resulted in increased PD-L1 expression. The experimental data suggest that PD-L1 may act as an upstream regulator of NBS1 and may facilitate formation of the MRN complex, enhancing repair of cisplatin induced DNA damage, thereby increasing the cell's resistance to chemotherapeutics. Decreasing expression of PD-L1 via siRNA leads to increased sensitivity of HNSCC cells to cisplatin. This highlights the importance of PD-L1 in the development of chemoresitance and suggests a potential therapeutic strategy for patients with cisplatin-resistant HNSCC. In conclusion, we have identified a novel role for PD-L1 in the development of chemoresistance through its interaction with the MRN complex, which plays a major role in the repair of chemo-induced DNA DSB. Therapies aimed at blocking PD-L1 show great promise because of their ability to enhance both chemotherapeutics and the anti-tumor immune response. Citation Format: Randall S. Ruffner, Andrew Ramsey, Bert W. O'Malley, Daqing Li. PD-L1 regulates cisplatin chemoresistance in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5474. doi:10.1158/1538-7445.AM2015-5474