Abstract 3721: EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination in colorectal cancer

Abstract The regulation of PD-L1 is the key question which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. The epigenetic mechanism is involved in transcriptional regulation towards PD-L1. However, besides the transcription level, the protein stability of PD-L1 is closely correlated to its function and has drawn more and more attention. In this study, EZH2 inhibition could enhance PD-L1 expression and protein stability, and the deubiquitinase ubiquitin-specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition upregulates the expression of USP22 via canonical mechanism, and upregulated USP22 further stabilize PD-L1. Importantly, a combination of EZH2 inhibitors with anti-PD-1 immune checkpoint blockade therapy could improve the tumor microenvironment, promotes immune cell infiltration, enhances sensitivity to immunotherapy and exerts synergistic anti-cancer effects. In addition, knocking down USP22 could potentially enhance the therapeutic efficacy of EZH2 inhibitor on colon cancer. These findings unveil the novel role of EZH2 inhibitors (EZH2i) in tumor immune evasion by upregulating PD-L1. Although it may be one reason of EZH2i inefficacy due to the fact that it elicits the immune suppressive effect, appropriately utilizing this drawback to arouse PD-L1 expression may convert the tumor into more responsive upon ICI cancer therapy. In addition, the EZH2-USP22-PD-L1 regulatory axis could further facilitating to identify populations sensitive to immunotherapy or provide novel strategy for combined treatment. Therefore, these findings provide valuable insights into the intricate interplay between EZH2 and PD-L1, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment. Citation Format: Jianling Yang, Jiaqi Huang, Qianqian Yin, Lixiang Xue. EZH2 inhibition enhances PD-L1 protein stability through USP22-mediated deubiquitination in colorectal cancer 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 (6Suppl): Abstract nr 3721.