Abstract 102: LMP1-mediated recruitment of ALIX directs exosomal PD-L1 sorting and contributes to immunosuppression in EBV+ nasopharyngeal carcinoma

Abstract Epstein-Barr virus (EBV) is known to cause multiple cancers and plays a pivotal role in tumor immune evasion. Latent membrane protein 1 (LMP1) is a key viral oncoprotein expressed in most EBV-associated cancers and contributes to tumor microenvironment remodeling. However, the exact role of LMP1 in modulating tumor immunity remains unclear. In this study, we elucidate how LMP1 interacts with PD-L1 and ALIX to form a trimolecular complex, facilitating the selective sorting of PD-L1 into exosomes and consequently impairing CD8+ T cell function in nasopharyngeal carcinoma (NPC). Specifically, the transmembrane domain of LMP1 interacts with and stabilizes PD-L1, while the intracellular domain of LMP1 binds to ALIX, thus enabling access to the exosomal secretory pathway. This interaction leads to the formation of a trimolecular complex comprising LMP1, PD-L1, and ALIX, which is indispensable for the exosomal trafficking of PD-L1. Importantly, disrupting ALIX significantly diminishes LMP1-induced exosomal PD-L1 secretion, thereby restoring CD8+ T cell functionality. Furthermore, we found that elevated levels of LMP1/ALIX expression are positively associated with immunosuppressive characteristics and poorer outcomes in human NPC. Our findings highlight the crucial role of the LMP1/ALIX axis in exosomal PD-L1 sorting and EBV-mediated immune evasion, presenting a novel and promising target for cancer immunotherapy. Citation Format: Fajian He, Yan Gong, Yajuan Zhou, Conghua Xie. LMP1-mediated recruitment of ALIX directs exosomal PD-L1 sorting and contributes to immunosuppression in EBV+ nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 102.