Wnt3a is a central regulator for P. gingivalis-mediated expression of PD-L1 and suppression of CD8+ T cell activity

点击翻译按钮获取中文摘要

Abstract Blockade of program death ligand-1 (PD-L1) is demonstrating remarkable clinical outcomes for patients with cancer or chronic infection through reinvigorating exhausted CD8+ T cell responses. However, only a small portion of patients can respond well to this treatment, indicating a dire need for an in-depth understanding of the function and regulatory mechanisms of PD-L1. Recent breakthrough findings revealed that expression of PD-L1 on dendritic cells (DCs) is critical for the efficacy of PD-L1/PD-1 blockade immunotherapy. Porphyromonas gingivalis (Pg) is a causative agent of chronic periodontal inflammation and tissue damages. Infection with Pg was reported to aggravate cancer progression and promote PD-L1 expression in tumor cells. However, if and how Pg infection promotes expression of PD-L1 on DCs and its possible effect on CD8+ T cell activity remain entirely unknown. Thus, it is tempting to identify novel immune signaling modulators that can regulate expression of PD-L1 and impact cytotoxic T cell activity, with a long-term goal of restoring the immune system function in surveillance and elimination of invaded organisms and cancer cells. Our recent studies demonstrated that Pg infection robustly increases expression of Wnt (Winglesss and Int-1) 3a in innate immune cells and Wnt3a negatively regulates the intensity of innate immune responses. Our preliminary data suggest that Pg infection (i) significantly enhances PD-L1 expression on BMDCs and impairs cytotoxicity of allogenic antigen-specific CD8+ T cells; (ii) remarkably enhances expression of Wnt3a, and inhibition of Wnt3a reduces expression of PD-L1 on BMDCs; and (iii) leads to an increase of Yes-associated protein 1(YAP) and WW- domain-containing transcription regulator-1(TAZ) expression but a decrease of an upstream kinase phosphorylation in DCs. Since YAP/TAZ was shown to associate with PD-L1 expression and interact with Wnt3a signaling in other contexts, we thus hypothesize that Wnt3a is a critical immunomodulator that promotes PD-L1 expression and suppresses CD8+ T cell activity upon stimulation with Pg by regulating activation of YAP/TAZ signaling and its downstream transcriptional enhancer factor (TEA)-domain family of DNA- binding factor 1 (TEAD1). We will demonstrate this hypothesis with two specific aims: (1): Establish the role of Wnt3a as an endogenous regulator of the Pg-induced PD-L1 and impairment of CD8+ T cell activity; (2) Establish if Wnt3a promotes Pg-induced PD-L1 expression and impairment of CD8+ T cell activity via modifying the activity of YAP/TAZ and its downstream TEAD1. Successful completion of this project will (i) maps out a novel and potentially critical signaling pathway (Wnt3a-YAP/TAZ-TEAD1) and identifies more interventional targets in PD-L1 expression; and (ii) greatly aids in understanding the regulatory mechanism that Pg infection impairs CD8+ T cell cytotoxicity, which will pave the way for the development of innovative immunoregulatory therapies for the control of cancer and chronic infections via manipulating activity of Wnt3- YAP/TAZ that should have relevance well beyond oral cavity.