Poster #28: Timothy Purwin PhD

Gene signature reveals YAP/TAZ/TEAD activity may influence ICi response by modulating MHC antigen processing and presentation machinery in melanoma

Timothy J. Purwin, PhD1, Kristen M. DeRosa1, Dan A. Erkes, PhD1, 2, and Andrew E. Aplin, PhD1, 2. 1 Department of Pharmacology, Physiology & Cancer Biology, 2 Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Despite advances in treatment, many cancer patients develop resistance or fail to respond to immune checkpoint inhibitor (ICi) therapies. While YAP/TAZ/TEAD-mediated expression has been linked to treatment resistance in cancer, its role in response to ICi remains unclear. We used computational methods to determine if there is a link between YAP/TAZ/TEAD activity and response to ICi therapy in melanoma, an immunogenic type of cancer. We combined RNAseq data from YAP knockdown (siYAP), TAZ knockdown (siTAZ), and TEAD inhibitor (TEADi) treated melanoma cell models to develop a YAP/TAZ/TEAD gene signature, validated it using an independent TEAD1–4 knockdown RNAseq dataset, and confirmed the changes occurred at the protein level in siTAZ LC-MS data. In patient scRNA-seq datasets, YAP/TAZ/TEAD scores were elevated in ICi-resistant tumors, and matched pre‑ and on‑treatment samples showed YAP/TAZ/TEAD scores decreased early during ICi therapy in responders. Investigation into immune-related pathways and ICi resistance mechanisms revealed positive enrichment of MHC Antigen Processing and Presentation in siYAP, siTAZ and TEADi data. We activated TAZ using a doxycycline‑inducible TAZ S89A model and observed negative enrichment of MHC Antigen Processing and Presentation in RNAseq data. In siTAZ LC-MS data, several changes were confirmed in key MHC Antigen Processing and Presentation pathway proteins. Further investigation into patient scRNAseq datasets revealed YAP/TAZ/TEAD scores inversely correlated with MHC Antigen Processing and Presentation gene signature scores. These findings suggest TEAD activity may influence ICi response, in part, due to modulation of MHC Antigen Processing and Presentation machinery.