Programmed death-ligand 1 (PD-L1), expressed on the surface of tumor cells, can bind to programmed cell death-1 (PD-1) on T cells. The interaction of PD-1 and PD-L1 can inhibit T-cell responses by decreasing T-cell activity and accelerating their apoptosis. Various cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T-cell immunity, and immunotherapies targeting the PD-1/PD-L1 axis have been shown to exert remarkable anti-tumor effects; however, not all tumor patients benefit from these therapies. Therefore, study of the mechanisms regulating PD-L1 expression are imperative. In this review, we explore regulation of PD-L1 expression in the contexts of gene transcription, signaling pathways, histone modification and remodeling, microRNAs, long noncoding RNAs, and post-translational modification. Current developments in studies of agents that block PD-L1 and correlations between immunotherapies targeting PD-1/PD-L1 and PD-L1 expression are also summarized. Our review will assist in understanding of PD-L1 expression regulation and discusses the implications of reported findings in cancer diagnosis and immunotherapy.

Natural killer (NK) cells exhibit antifibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin E2 (PGE2) plays a dual role in innate and adaptive immunity. Here, we found that E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell–specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. Loss of EP3 selectively reduced the cytotoxicity of the CD27+CD11b+ double positive (DP) NK subset against activated HSCs. Mechanistically, deletion of EP3 impaired the adhesion and cytotoxicity of DP NK cells toward HSCs through modulation of Itga4-VCAM1 binding. EP3 upregulated Itga4 expression in NK cells through promoting Spic nuclear translocation via PKC-mediated phosphorylation of Spic at T191. Activation of EP3 by sulprostone alleviated CCL4-induced liver fibrosis in mice. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.

Background/Aims: The incidence of gastric cancer (GC) ranks fifth among common tumors and GC is the third leading cause of cancer-related death worldwide. The aim of this study was to develop and validate a nomogram for predicting the overall survival (OS) of patients with GC.

MAVS is a critical adaptor required for activating an innate antiviral immune response against viral infection. The activation of MAVS requires modification of the Lys63-linked ubiquitination and formation of prion-like aggregates. However, the molecular mechanisms regulating MAVS activity remain largely obscured. In this study, we identified a deubiquitinase YOD1, also known as a member of the ovarian tumor family, as a negative regulator of MAVS activation in both human and murine cells. YOD1 was recruited to mitochondria to interact with MAVS through its UBX and Znf domains after viral infection. Subsequently, YOD1 cleaved the K63-linked ubiquitination and abrogated the formation of prion-like aggregates of MAVS, which led to attenuation of IRF3, P65 activation, and IFN-β production. Knockdown of YOD1 potentiated IRF3 and P65 activation, IFN-β production, and antiviral innate immune response to RNA virus. Our findings thus provided, to our knowledge, novel insights into the regulatory cascade of the cellular antiviral response through YOD1-mediated K63-linked deubiquitination and aggregation of MAVS.

Gut microbiota-derived butyrate plays a vital role in attenuating hepatocellular carcinoma (HCC) in murine models. However, the precise molecular mechanisms by which butyrate exerts its effects are largely undefined. Plasma short-chain fatty acids (SCFAs) were quantitatively measured by using gas chromatography-mass spectrometry (GC-MS) to access their association with HCC prognosis. Tumor-infiltrating immune cells were characterized by flow cytometry. The interactions between butyrate and natural killer (NK) cells were studied using in vitro assays, including migration, cytotoxic degranulation, and co-culture experiments. In vivo validation was conducted through neutralization experiments. The molecular pathways regulated by butyrate were further investigated by employing RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). A positive correlation was observed between elevated plasma butyrate levels and improved prognosis in HCC patients. Notably, butyrate inhibited tumor progression by enhancing NK cell infiltration into tumor tissues. Mechanistically, butyrate stimulated cytokine secretion, notably significantly enhancing the production of the chemokine CXCL11, thereby facilitating NK cell infiltration. Gene Set Enrichment Analysis (GSEA) of hepatic tumor cell lines revealed that the chemokine signaling and NK cell-mediated cytotoxicity pathways were upregulated following butyrate stimulation. Furthermore, transcriptomic and epigenomic analyses showed that exposure to butyrate induced de novo chromatin accessibility and enhancer remodeling, regulated by STAT family transcription factors. Our study demonstrated that butyrate was able to enhance the expression of CXCL11. This is likely attributed to chromatin remodeling, and then promoting NK cell infiltration and exerting effective anti-tumor effects on HCC.

Natural killer (NK) cells are critical innate lymphocytes that can directly kill target cells without prior immunization. NK cell activation is controlled by the balance of multiple germline-encoded activating and inhibitory receptors. NK cells are a heterogeneous and plastic population displaying a broad spectrum of functional states (resting, activating, memory, repressed, and exhausted). In this review, we present an overview of the epigenetic regulation of NK cell-mediated antitumor immunity, including DNA methylation, histone modification, transcription factor changes, and microRNA expression. NK cell-based immunotherapy has been recognized as a promising strategy to treat cancer. Since epigenetic alterations are reversible and druggable, these studies will help identify new ways to enhance NK cell-mediated antitumor cytotoxicity by targeting intrinsic epigenetic regulators alone or in combination with other strategies.