Lisha Li

Bio: Lisha Li is an academic researcher from Harbin Medical University. The author has contributed to research in topics: Pyroptosis & PKM2. The author has an hindex of 3, co-authored 7 publications receiving 45 citations.

Pyroptosis, a new bridge to tumor immunity

Abstract: Pyroptosis refers to the process of gasdermin (GSDM)-mediated programmed cell death (PCD) and our understanding of pyroptosis has expanded beyond the cells and is known to involve extracellular responses. Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis-mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double-edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome-mediated pyroptosis and the release of pyroptosis-produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis-produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also closely with several immune checkpoints, especially programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1). In this review, we mainly focused on our current understanding of the interplay between the immune system and tumors that process through pyroptosis and debate about their use as potential therapeutic targets.

Role of GSDMB in Pyroptosis and Cancer

Abstract: Gasdermin B (GSDMB) belongs to the gasdermin (GSDM) family which may adopt different mechanisms of intramolecular domain interactions to modulate their lipid-binding and pore-forming activities. The GSDM family has regulatory functions in cell proliferation and differentiation, especially in pyroptosis process. Pyroptosis is a pro-inflammatory form of regulated cell death and is designed to attract a nonspecific innate response to the site of infection. For cancer cells, the activation of pyroptosis may promote cell death and exert anticancer properties. Also, recent studies have observed the pyroptosis-like features in GSDMB and some researches have shown that GSDMB overexpression occurred in several kinds of cancers ; these findings bring a contradiction with the participation of GSDMB in pyroptosis. Although people pay less attention to GSDMB, it still has some essential research value. It is a paradox that GSDMB might participate in programmed cell death, which might put forward a research direction of therapeutic targets for cancer. Here, we review the possible progress of how GSDMB participated in this inflammatory regulation mechanistically and the potential functions of GSDMB in cancer.

Switching from Apoptosis to Pyroptosis: Gasdermin-Elicited Inflammation and Antitumor Immunity.

Abstract: Pyroptosis is a necrotic form of regulated cell death. Gasdermines (GSDMs) are a family of intracellular proteins that execute pyroptosis. While GSDMs are expressed as inactive forms, certain proteases proteolytically activate them. The N-terminal fragments of GSDMs form pores in the plasma membrane, leading to osmotic cell lysis. Pyroptotic cells release pro-inflammatory molecules into the extracellular milieu, thereby eliciting inflammation and immune responses. Recent studies have significantly advanced our knowledge of the mechanisms and physiological roles of pyroptosis. GSDMs are activated by caspases and granzymes, most of which can also induce apoptosis in different situations, for example where the expression of GSDMs is too low to cause pyroptosis; that is, caspase/granzyme-induced apoptosis can be switched to pyroptosis by the expression of GSDMs. Pyroptosis appears to facilitate the killing of tumor cells by cytotoxic lymphocytes, and it may also reprogram the tumor microenvironment to an immunostimulatory state. Understanding pyroptosis may help the development of cancer immunotherapy. In this review article, recent findings on the mechanisms and roles of pyroptosis are introduced. The effectiveness and limitations of pyroptosis in inducing antitumor immunity are also discussed.

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Abstract: In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune "cold" tumors into "hot" tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.

Single-cell RNA-seq reveals cell type–specific molecular and genetic associations to lupus

Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon–stimulated genes (ISGs) in monocytes, reduction of naïve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH+ CD8+ T cells. Cell type–specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type–specific cis–expression quantitative trait loci and to link SLE-associated variants to cell type–specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE. Description INTRODUCTION Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with elevated prevalence in women and individuals of Asian, African, and Hispanic ancestry. Bulk transcriptomic profiling has implicated increased type 1 interferon signaling, dysregulated lymphocyte activation, and failure of apoptotic clearance as hallmarks of disease. Many genes participating in these processes are proximal to the ~100 loci associated with SLE. Despite this progress, a comprehensive census of circulating immune cells in SLE remains incomplete, and annotating the cell types and contexts that mediate genetic associations remains challenging. RATIONALE Historically, flow cytometry and bulk transcriptomic analyses were used to profile the composition and gene expression of circulating immune cells in SLE. However, flow cytometry is biased by its use of a limited set of known markers, whereas bulk transcriptomic profiling does not have sufficient power to detect cell type–specific expression differences. Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) holds potential as a comprehensive and unbiased approach to simultaneously profile the composition and transcriptional states of circulating immune cells. However, application of scRNA-seq to population cohorts has been limited by sample throughput, cost, and susceptibility to technical variability. To overcome these limitations, we previously developed multiplexed scRNA-seq (mux-seq) to enable systematic and cost-effective scRNA-seq of population cohorts. RESULTS We used mux-seq to profile more than 1.2 million PBMCs from 162 SLE cases and 99 healthy controls of either Asian or European ancestry. SLE cases exhibited differences in both the composition and state of PBMCs. Analysis of lymphocyte composition revealed a reduction in naïve CD4+ T cells and an increase in repertoire-restricted GZMH+ CD8+ T cells. Analysis of transcriptomic profiles across eight cell types revealed that classical monocytes expressed the highest levels of both pan–cell type and myeloid-specific type 1 interferon–stimulated genes (ISGs). The expression of ISGs in monocytes was inversely correlated with naïve CD4+ T cell abundance. Cell type–specific expression features accurately predicted case-control status and stratified patients into molecular subtypes. By integrating genotyping data and using a novel matrix decomposition method, we mapped shared and cell type–specific cis–expression quantitative trait loci (cis-eQTLs) across eight cell types. Cell type–specific cis-eQTLs were enriched for regions of open chromatin specific to the same or related cell types. Joint analysis of cis-eQTLs and genome-wide association study results enabled identification of cell types relevant to immune-mediated diseases, fine-mapping of disease-associated loci, and discovery of novel SLE associations. Interaction analysis identified variants whose effects on gene expression are further modified by interferon activation across patients. CONCLUSION SLE remains challenging to diagnose and treat. The heterogeneity of disease manifestations and treatment response highlight the need for improved molecular characterization. In a large multiethnic cohort, we demonstrate mux-seq as a systematic approach to characterize cellular composition, identify cell type–specific transcriptomic signatures, and annotate genetic variants associated with SLE. Detection of cellular and genetic correlates of SLE. Genetic multiplexing enabled single-cell profiling of hundreds of individuals with and without SLE. These profiles revealed that SLE patients exhibit changes in cell composition and cell type–specific gene expression, which were used to model disease status and severity. Additionally, cell type–specific cis-eQTL maps were produced and used to annotate and contextualize genetic loci associated with SLE. Analyzing immune system gene expression Diseases involving the immune system are heritable, but it is unknown how genetic variation contributes to different diseases. To identify how implicated loci affect gene expression in immune cells from individuals from different populations, two groups performed single-cell RNA sequencing of immune cells, with each study investigating hundreds of individuals and more than 1 million immune cells (see the Perspective by Sumida and Hafler). These studies examined both proximal (cis) and distal (trans) genetic variants affecting gene expression in 14 different immune cell types. Perez et al. studied healthy individuals of both European and Asian descent, as well as individuals diagnosed with systemic lupus erythematosus. Yazar et al. performed a population-based study investigating how segregating alleles contribute to variation in immune function. Integrating these data with autoimmune disease cohorts identifies causal effects for more than 160 loci. Both studies observe how gene expression patterns are cell-type and context specific and can explain observed variation in immune cell function among individuals. Both studies also identify causal links between genome-wide analyses and expression quantitative trait loci, identifying potential mechanisms underlying autoimmune diseases. —LMZ Single-cell sequencing identifies genetic variants associated with systemic lupus erythematosus.

Pyroptosis, a new bridge to tumor immunity

Abstract: Pyroptosis refers to the process of gasdermin (GSDM)-mediated programmed cell death (PCD) and our understanding of pyroptosis has expanded beyond the cells and is known to involve extracellular responses. Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis-mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double-edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome-mediated pyroptosis and the release of pyroptosis-produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis-produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also closely with several immune checkpoints, especially programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1). In this review, we mainly focused on our current understanding of the interplay between the immune system and tumors that process through pyroptosis and debate about their use as potential therapeutic targets.

Pyroptosis at the forefront of anticancer immunity.

Abstract: Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention. Pyroptosis, a lytic and inflammatory programmed cell death pathway distinct from apoptosis, has subsequently sparked notable interest among cancer researchers for its potential to be clinically harnessed and to address these problems. Recent evidence indicates that pyroptosis induction in tumor cells leads to a robust inflammatory response and marked tumor regression. Underlying its antitumor effect, pyroptosis is mediated by pore-forming gasdermin proteins that facilitate immune cell activation and infiltration through their release of pro-inflammatory cytokines and immunogenic material following cell rupture. Considering its inflammatory nature, however, aberrant pyroptosis may also be implicated in the formation of a tumor supportive microenvironment, as evidenced by the upregulation of gasdermin proteins in certain cancers. In this review, the molecular pathways leading to pyroptosis are introduced, followed by an overview of the seemingly entangled links between pyroptosis and cancer. We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies.