Targeting Pd-L1 Sensitizes Head And Neck Squamous Cell Carcinoma To Cisplatin

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Platinum-based chemotherapy agents such as Cisplatin (CDDP) are commonly used as first-line treatment for several types of human cancers including ovarian, lung, testicular, and head and neck squamous cell carcinomas (HNSCC). Unfortunately, CDDP monotherapy is often ineffective due to inherent or acquired tumor resistance to therapy, also known as chemoresistance. This contributes to a need for the administration of larger, more toxic doses, as well as failure of chemotherapy and tumor recurrence. Despite the clinical significance of chemoresistance, the mechanisms driving this phenomenon are not completely understood. Programmed cell death ligand 1 (PD-L1), a membrane-bound glycoprotein responsible for modulating the immunological response through the induction of T-Cell anergy and apoptosis, has been shown to be overexpressed in many cancers, including HNSCC. While PD-L1 overexpression has been directly related to the immunoevasion of cancer cells allowing for tumor progression, recent reports suggest that PD-L1 also plays an important role in the tumor response to doxorubicin-based chemotherapy independent of its immune function. The present study investigates the role of PD-L1 in response to CDDP in HNSCC. In vitro experiments were performed using four well-characterized human HNSCC cell lines. Quantitative polymerase chain reaction (qPCR) and western blot were conducted to determine the baseline and post-CDDP-treatment PD-L1 gene expression. The results demonstrated that PD-L1 mRNA transcription and protein expression are upregulated in response to CDDP, suggesting that PD-L1 is involved in the chemoresponse. Conversely, knockdown of PD-L1 using siRNA resulted in chemosensitization of HNSCC cells to CDDP. Together, these findings implicate PD-L1 in the CDDP-chemoresponse in HNSCC. In conclusion, we propose a role for PD-L1 that is distinct from the classic immunoevasion pathway. Our findings demonstrate that disruption of this protein leads to increased sensitivity of HNSCC cells to CDDP, suggesting a potential combination therapeutic strategy for patients with CDDP-resistant HNSCC. Citation Format: Peter Qiao, Shayanne A. Lajud, Danish A. Nagda, Nobuaki Tanaka, Alyssa Civantos, Bert W. O'Malley, Daqing Li. Targeting PD-L1 sensitizes head and neck squamous cell carcinoma to cisplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3750. doi:10.1158/1538-7445.AM2014-3750