T cell senescence and exhaustion represent critical aspects of adaptive immune system dysfunction, with profound implications for health and the development of disease prevention and therapeutic strategies. These processes, though distinct, are interconnected at the molecular level, leading to impaired effector functions and reduced proliferative capacity of T cells. Such impairments increase susceptibility to diseases and diminish the efficacy of vaccines and treatments. Importantly, T cell senescence and exhaustion can dynamically influence each other, particularly in the context of chronic diseases. A deeper understanding of the molecular mechanisms underlying T cell senescence and exhaustion, as well as their interplay, is essential for elucidating the pathogenesis of related diseases and restoring dysfunctional immune responses. This knowledge will pave the way for the development of targeted therapeutic interventions and strategies to enhance immune competence. This review aims to summarize the characteristics, mechanisms, and disease associations of T cell senescence and exhaustion, while also delineating the distinctions and intersections between these two states to enhance our comprehension.

Patients with cirrhosis are at an increased risk of bacterial infection (BI), which is the most common precondition for acute-on-chronic liver failure (ACLF). In this study, we aimed to evaluate the ability of mitochondria-related indicators (mitochondrial mass and mitochondrial membrane potential (MMP)) of T cells in peripheral blood to predict BI and ACLF within 90 days in cirrhotic patients.

We prospectively studied mitochondria-related indicators in various T cells from 235 cirrhotic patients at the Second Hospital of Nanjing. The outcomes of interest were BI and ACLF.

The restricted cubic spline analysis showed that the MMP of CD8+ T cells had a linear relationship with the risk of BI and ACLF (both P < 0.001). Multivariable Cox regression analysis demonstrated that the MMP of CD8+ T cells was an independent risk factor for both BI and ACLF (BI: hazard ratio 0.96, 95% confidence interval 0.94-0.98; P < 0.001; ACLF: hazard ratio 0.94, 95% confidence interval 0.90-0.97; P < 0.001). The MMP of CD8+ T cells exhibited better diagnostic efficacy than traditional indices in predicting BI (C index: 0.75). The MMP of CD8+ T cells, when combined with traditional models (Child-Turcotte-Pugh and model for end-stage liver disease score), improved their diagnostic efficiency in predicting both BI and ACLF. Additionally, the MMP of CD8+ T cells showed a significant negative correlation with inflammation-related markers (P < 0.05). Mitochondrial damage and abnormally activated mitochondrial autophagy were observed in CD8+ T cells from cirrhotic patients with low MMP.

The MMP of CD8+ T cells could serve as a valuable predictor of BI and ACLF within 90 days in cirrhotic patients.

Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled spleens of nonhuman primates (NHPs) on varying degrees of immunosuppression. We found evidence that konjac glucomannan-modified silica nanoparticles (KSiNPs) remodeled the spleen into an extracellular matrix (ECM)-rich, immunosuppressive niche to support the survival of syngeneic or xenogeneic islets. Transplanted islets in the remodeled spleens showed improved engraftment, neovascularization, and functionality and restored normoglycemia in streptozotocin (STZ)-induced type 1 diabetic models in the mice and macaques, with stable insulin and C-peptide secretion in mice for 90 days and macaques for 28 days. KSiNP injection and islet transplantation into macaque spleens under B-ultrasound guidance were preclinically feasible. These findings highlight the safety and effectiveness of spleen tissue remodeling in supporting the survival and function of transplanted islets, providing a promising strategy for treating type 1 diabetes mellitus (T1DM).

T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction.

A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.

In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression.

Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.

In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.

Allergic asthma in children is typically associated with house dust mites (HDM) as the key allergen. Nevertheless, the diagnostic rate remains below 60% due to the absence of specific symptoms and diagnostic markers, which hinders the implementation of targeted personalized therapies. This study investigates immunological features of asthma with house dust mite (HDM) sensitisation in children, aiming to uncover diagnostic markers at single-cell resolution. The cohort comprised 8 children with physician-diagnosed asthma (age range: 4-11 years), stratified into groups based on HDM sensitization status. Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) was conducted, employing Seurat for cell identification and differential gene expression analysis. Enrichment analyses and LASSO regression identified signature genes related to cellular origin, with protein-protein interaction networks elucidating cellular communication differences between groups. A total of 11 distinct cell types were identified, with classical monocytes and monocytes being the predominant cell types that differentiated the two groups. Among these, 12 genes were up-regulated, and 40 down-regulated, mainly involving MHC-II complex and antigen presentation pathways, as validated by Gene Ontology and Gene Set Enrichment Analysis. The machine learning model accurately predicted cellular groupings, evidenced by an area under the curve of 0.83. Enhanced communication signals in HDM allergy cases involved monocytes, contrasting with reduced interactions in naive CD8 + cells. HLA-DR and HLA-DP were identified as the primary hallmark receptors, and the innate immunity differences with non-dust mite allergic asthma were characterized by 18 genes including top candidates MT-ND4 and RPS3A. Individuals with HDM-sensitized asthma exhibited altered expression of MHC-II complex genes in their PBMCs and distinct gene expression patterns in antigen-presenting cells, highlighting the critical role of HLA-DR and HLA-DP in the HDM allergen presentation.

Gastric cancer (GC) is a malignant tumor with one of the highest morbidity and death rates in the world. Neoadjuvant therapy, including neoadjuvant chemotherapy (NAC) and NAC combined with immunotherapy, can improve the resection and long-term survival rates. However, not all patients respond well to neoadjuvant therapy. It has been confirmed that immune cells in the tumor immune microenvironment, including T cells, B cells, and natural killer cells, can affect the efficacy of neoadjuvant therapy. This paper summarizes current preclinical and clinical evidence to more fully describe the effects of neoadjuvant therapy on the immune microenvironment of GC, to provide the impetus to identify biomarkers to predict the potency of neoadjuvant therapy, and to identify the mechanisms of drug resistance, which should promote the development of individualized and accurate treatments for GC patients.

The incidence rate of COVID-19-associated pulmonary aspergillosis (CAPA) is rising. However, the pathogenesis of CAPA remains unclear. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection disrupts pathways related to type I interferon and Toll-like receptors, key components in innate immunity, thereby elevating the incidence of CAPA. Additionally, SARS-CoV-2 infection results in T and B cell functional deficiencies or exhaustion within adaptive immunity, weakening the defense against invasive Aspergillus. Furthermore, SARS-CoV-2 infection enhances the replication of cytomegalovirus and alters the gut microbiota, factors that may aid in diagnosing CAPA. Immunosuppressive therapy in COVID-19 patients is also believed to heighten the risk of invasive aspergillosis. Therefore, this review, examines the immune response to SARS-CoV-2 infection combined with invasive aspergillosis, and explores the pathogenesis and susceptibility factors of CAPA. We propose that variations in an individual's immune response significantly determine susceptibility to CAPA. The aim of this paper is to deepen clinical understanding of CAPA's pathogenesis, thereby aiding in mitigating susceptibility risk and advancing novel treatment approaches.

T-cell senescence occurs in the tumor microenvironment (TME) and influences cancer outcomes as well as the effectiveness of immunotherapies. The TME triggers this T-cell senescence via multiple pathways, including persistent stimulation with tumor-associated antigens, altered metabolic pathways, and activation of chronic inflammatory responses. Senescent T cells exhibit characteristics such as genomic instability, loss of protein homeostasis, metabolic dysregulation, and epigenetic alterations. Direct cross-talk between senescent T cells and other immune cells further exacerbates the immunosuppressive TME. This immune-tumor cell interaction within the TME contributes to impaired tumor antigen recognition and surveillance by T cells. The presence of senescent T cells is often associated with poor prognosis and reduced efficacy of immunotherapies; thus, targeting the tumor-promoting mechanisms of T-cell senescence may provide novel insights into improving tumor immunotherapy and patient outcomes. This review explores the contributors to tumor-derived T-cell senescence, the link between T-cell senescence and tumor prognosis, and the potential for targeting T-cell senescence to enhance tumor immunotherapy.

Extracellular vesicles (EVs) play a vital role in intercellular communication within the tumor microenvironment (TME). These vesicles, secreted by tumor cells, contain proteins, lipids, and nucleic acids that significantly influence immune responses, particularly impacting T-cell function. In cancer, T cell dysfunction and exhaustion-marked by reduced proliferation, diminished cytokine production, and impaired cytotoxic activity-are key barriers to effective immune responses. Tumor-derived extracellular vesicles (TEVs) contribute to this dysfunction by carrying immunosuppressive molecules, such as transforming growth factor-beta (TGF-β) and various microRNAs (miRNAs). These TEV-mediated mechanisms promote T cell exhaustion and foster a broader immunosuppressive environment, enabling tumor progression and immune evasion. Furthermore, TEVs have been implicated in resistance to cancer immunotherapies, including immune checkpoint inhibitors and T cell therapies. Understanding the molecular pathways and cargoes within TEVs that drive T cell dysfunction is crucial for developing novel therapeutic strategies aimed at reinvigorating exhausted T cells, enhancing anti-tumor immunity, and improving cancer treatment outcomes.

Crosstalk between the nervous system and the immune system shapes the tumor microenvironment. Cholinergic T cells, a unique population of T cell antigen receptor-induced acetylcholine-producing T cells, have emerged as an integrative interface between these two fundamental body systems. Here we review the distinct characteristics and functions of cholinergic T cells in cancer settings. We first outline the expression of choline acetyltransferase and the cholinergic machinery in T cells. We then describe the dysfunctional state of choline acetyltransferase-expressing T cells in cancer and delve into their modulatory effects on T cells, cancer cells and the tumor microenvironment, including its populations of immune cells, its vasculature and its nerves. We also discuss the clinical implications of harnessing the potential of cholinergic T cells and future directions for increasing our understanding of their importance and possible exploitation.

Despite significant advances in cancer biology research and treatment, clinical outcomes for patients with liver cancer remain unsatisfactory. The biological and molecular mechanisms underlying the bidirectional signaling between tumor cells and the tumor microenvironment (TME), which promotes tumor progression in the liver, remain to be elucidated. Fibroblasts are crucial regulators of tumor progression and response to therapy; however, our understanding of their roles remains limited. Here, we integrated single-cell RNA sequencing and spatial transcriptomic data of pan-liver cancers to characterize the different subtypes of cancer-associated fibroblasts (CAFs). siRNA transfection was used for knockdown the expression of LAMA4. Western blot assay was used for gene expression analysis. Flow cytometry was used to detect proliferation, toxicity and cytolytic capacity of CD8+ T cells. To establish a spontaneous murine hepatocellular carcinoma (HCC) model, a combined DEN and CCL4 approach was performed. Notably, we identified CD90+ extracellular matrix CAFs (eCAFs) associated with poor prognosis. These CD90+ eCAFs, located distal to the tumor nest, overlapped with the distribution of CD8+ T cells. Functional experiments demonstrated that CD90+ eCAFs recruited CD8+ T cells and inhibited their function through secretion of LAMA4. Further investigation revealed that LAMA4 induced the CD8+ T cell senescence through a DNA damage signaling pathway mediated by the receptor ITGA6. In a mouse model of spontaneous HCC, targeting LAMA4 can inhibit the progression of malignant transformation and synergize with anti-PD-1 therapy. Our study reveals the function of specific CAFs subtypes and highlights the importance of interactions with the immune system.

Vδ2 T cells, a predominant human peripheral γδ T cell population, are a promising candidate for the development of immunotherapies against cancer and infected cells. Aminobisphosphonate drugs, such as zoledronate, are commonly used to expand Vδ2 T cells. Yet, such in vitro generated cells have limited efficacy in the clinic. We found that despite inducing excessive proliferation of Vδ2 T cells, zoledronate impaired their effector function and caused the upregulation of the inhibitory receptor TIM3. This effect was due to the inhibition of mevalonate metabolism and dysregulation of downstream biological processes such as protein prenylation and intracellular signalling. In vitro and in vivo inhibition of mevalonate metabolism with zoledronate, statins, and 6-fluoromevalonate, as well as genetic deficiency of the mevalonate kinase, all resulted in compromised cytokine and cytotoxic molecule production by Vδ2 T cells. Impaired Vδ2 T cell function was accompanied by transcriptome and kinome changes. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vδ2 T cells. This observation provides important considerations for improving their therapeutic use and has repercussions for patients with statin or aminobisphosphonate treatments.

Ulcerative colitis (UC) is a nonspecific chronic inflammatory disease that occurs in the gastrointestinal tract and is characterized by the breakdown of mucosal immunity. T helper (Th) cells paradigm disequilibrium is a critical for pathogenesis. Maslinic acid (MA), a naturally occurring pentacyclic triterpene isolated from olive pomace and Fructus crataegi, has a variety of applications in both medicine and food. This study investigated the molecular mechanism of the anti-inflammatory potential of MA in a colitis model and activated Th cells. A dextran sulfate sodium-induced experimental colitis model was established. Clinical symptoms were evaluated, and biological samples were collected to examine intestinal mucosal function, inflammation levels, and Th cell-mediated immune responses. The mechanism of the activation-induced cell death (AICD) effect regulated by MA was investigated in the anti-CD3ε/CD28-stimulated Th cell activation model using molecular biotechnology and transcriptome analysis. Key results:MA treatment protected intestinal mucosa, which manifested as reduced inflammatory cytokines, Th cell infiltration, and subset differentiation. Additionally, it was found to suppress Th cell proliferation and differentiation of subsets, regulate cell cycle distribution, and promote AICD by regulating the mitochondria-mediated intrinsic pathway in vitro. JAK-STAT and FcεRI pathways were probable essential pathways, and MAF might be a crucial potential targeting molecule in activated Th cells with MA treatment. This finding demonstrated that MA induced remission of the colitis-related inflammation, which may depend on the resolution of acute inflammation by reducing Th cell-mediated inflammation via AICD induction, emphasizing its promising potential in the treatment of UC.

Unleashing T cell function is critical for efficacious cancer immunotherapy. Here, we present an in vivo T cell activation strategy by silencing Casitas B-lineage lymphoma proto-oncogene b (Cbl-b), an intracellular checkpoint, to effectively combat solid tumors. The polymersomes are able to efficiently load and deliver siRNA against cblb to T cells both in vitro and in vivo, successfully silencing the cblb gene expression in primary T cells and enhancing the IL-2 receptor CD25 expression, which in turn enhances T cell function and prevents T cell exhaustion. In vitro and in vivo studies showed that siRNA against cblb caused an effective inhibition of tumor progression in subcutaneous B16-F10 and LLC models, in which a significant increase of effector T cells in peripheral blood mononuclear cells and an increase of effector T cells and a significant decrease of Treg cells in the tumor were clearly observed. This polymersome-mediated down-regulation of the cblb gene in T cells provides a promising approach for activating T cells and enhancing their anti-tumor capacity.

The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.

In solid tumors, the tumor microenvironment (TME) is a complex mix of tumor, immune, stromal cells, fibroblasts, and the extracellular matrix. Cytotoxic T lymphocytes (CTLs) constitute a fraction of immune cells that may infiltrate into the TME. The primary function of these T-cells is to detect and eliminate tumor cells. However, due to the immunosuppressive factors present in the TME primarily mediated by Myeloid-Derived Suppressor Cells (MDSCs), Tumor associated macrophages (TAMs), Cancer Associated Fibroblasts (CAFs) as well as the tumor cells themselves, T-cells fail to differentiate into effector cells or become dysfunctional and are unable to eliminate the tumor. In addition, chronic antigen stimulation within the TME also leads to a phenomenon, first identified in chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, where the T-cells become exhausted and lose their effector functions. Exhausted T-cells (Tex) are characterized by the presence of remarkably conserved inhibitory receptors, transcription and signaling factors and the downregulation of key effector molecules. Tex cells have been identified in various malignancies, including melanoma, colorectal and hepatocellular cancers. Recent studies have indicated novel strategies to reverse T-cell exhaustion. These include checkpoint inhibitor blockade targeting programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), or combinations of different immune checkpoint therapies (ICTs) or combination of ICTs with cytokine co-stimulation. In this review, we discuss aspects of T-cell dysfunction within the TME with a focus on T-cell exhaustion. We believe that gaining insight into the mechanisms of T-cell exhaustion within the TME of human solid tumors will pave the way for developing therapeutic strategies to target and potentially re-invigorate exhausted T-cells in cancer.

After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet β-cells, significant research has recently demonstrated that β-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. SIGNIFICANCE STATEMENT: This research delves into the underlying causes of T1D and identifies critical mechanisms governing β-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting β-cells, (3) compounds that act simultaneously on both immune cell and β-cell pathways, and (4) combinations of compounds simultaneously targeting immune and β-cell pathways.

Chimeric antigen receptor (CAR)-T-cell therapy has garnered significant attention for its transformative impact on the treatment of hematologic malignancies such as leukemia and lymphoma. Despite its remarkable success, challenges such as resistance, limited efficacy in solid tumors, and adverse side effects remain prominent. This review consolidates recent advancements in CAR-T-cell therapy and explores innovative engineering techniques and strategies to overcome the immunosuppressive tumor microenvironment (TME). We also discuss emerging applications beyond cancer, including autoimmune diseases and chronic infections. Future perspectives highlight the development of more potent CAR-T cells with increased specificity and persistence and reduced toxicity, providing a roadmap for next-generation immunotherapies.

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL) that typically presents in the early phase as inflammatory erythematous patches or plaques, with epidermotropism as the histopathological hallmark of the disease. Traditionally, in the early stages, non-aggressive options represent the first-line strategy: topical corticosteroids, phototherapy, radiotherapy, and occasionally adopting a "wait-and-see" approach for minimally symptomatic patients. In patients with advanced or recurrent disease, good results can be achieved with immune modifiers, chemotherapeutic agents, total skin irradiation, or extracorporeal photochemotherapy, and maintenance therapy is often required. The past decade has seen an expansion of therapies that can be used in this setting by increasing new therapeutic strategies. The key advancements coming from recently published trials are resumed in this article.

Fungal microbes are a small but immunoreactive component of the human microbiome, which may influence cancer development, progression and therapeutic response. Immunosenescence is a process of immune dysfunction that occurs with aging, including lymphoid organ remodeling, contributing to alterations in the immune system in the elderly, which plays a critical role in many aspects of cancer. There is evidence for the interactions between fungi and immunosenescence in potentially regulating cancer progression and remodeling the tumor microenvironment (TME). In this review, we summarize potential roles of commensal and pathogenic fungi in modulating cancer-associated processes and provide more-detailed discussions on the mechanisms of which fungi affect tumor biology, including local and distant regulation of the TME, modulating antitumor immune responses and interactions with neighboring bacterial commensals. We also delineate the features of immunosenescence and its influence on cancer development and treatment, and highlight the interactions between fungi and immunosenescence in cancer. We discuss the prospects and challenges for harnessing fungi and immunosenescence in cancer diagnosis and/or treatment. Considering the limited understanding and techniques in conducting such research, we also provide our view on how to overcome challenges faced by the exploration of fungi, immunosenescence and their interactions on tumor biology.

CD8+ T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impede the T cell-intrinsic transcription of SLC7A5 and SLC38A1, disrupting aa transport and consequently leading to mTOR inactivation. Further, the ubiquitination of YAP1 protein is the basis for NSCLC-mediated transcriptional inhibition of aa transporters. Mechanistically, NSCLC cells transfer β-TrCP-containing exosomes into T cells, inducing YAP1 ubiquitination and Tex. Consequently, inhibiting cancer-associated β-TrCP effectively restores the anti-tumor immune response of CD8+ T cells and curtails tumor growth in NSCLC patient-derived organoids. Together, our findings highlight a β-TrCP-dependent mechanism in steering intrinsic metabolic adaptation and CD8+ Tex, emphasizing microenvironmental β-TrCP as an immune checkpoint for therapeutic exploration against human NSCLC.

Increased PD-1 expression on CD8+ T cells is considered as a hallmark for T-cell exhaustion, and is thought to be related to the prognosis of cancer patients. However, discrepant results have made it difficult to apply PD-1+CD8+T cells and tumor prognosis to clinical practice. Therefore, we conducted a meta-analysis to evaluate its prognostic value in human cancers.

PRISMA reporting guidelines were strictly followed for conducting the current meta-analysis. The PubMed, Web of Science, Embase databases were searched from inception to November 2024. The pooled Hazard Ratio (HR) along with 95% confidence intervals (CIs) of each article were combined for the associations of PD-1+CD8+ T cells with overall survival (OS), progression- free survival (PFS) and disease-free survival(DFS). Subgroup analyses were performed for area, specimen type, cancer type, treatment, detected method and cancer stage.

A total of 20 studies (23 cohorts, 3086 cancer patients) were included in our study. The expression PD-1+CD8+ T cells in cancer patients tended to predict poor overall survival (OS) (HR: 1.379, 95%CI: 1.084-1.753, p= 0.009), and unfavorable disease-free survival(DFS) (HR: 1.468, 95%CI: 0.931-2.316, p=0.099), though it did not reach statistical significance. Begg's and Egger's test demonstrated that no obvious publication bias was exist.

High PD-1 expression on CD8+ T cells is associated with worse survival outcomes, which can be potentially used as a prognostic marker of malignant tumor.

Bone marrow microenvironment plays an important role in promoting growth and survival of multiple myeloma (MM) cells. The tumor-promoting immune microenvironment is augmented while antitumor immune responses are inhibited. Although clinical and genomic markers of high-risk MM have been described, the immune status is just being recognized as a potential mediator of disease behavior. This is even more important with the development of a number of immune-based therapies. Based on these considerations, we evaluated peripheral blood absolute lymphocyte count (ALC) as an easily accessible marker representing immune microenvironment at diagnosis and after treatment of MM. We retrospectively evaluated 11 427 patients diagnosed with MM between 2000 and 2019 at Veterans Administration hospitals using ALC obtained closest to diagnosis and up to 2.5 years thereafter. Patients were stratified into 3 ALC categories: severely low, low, and normal (<1 × 103/μL, 1 × 103/μL to 1.5 × 103/μL, and >1.5 × 103/μL, respectively). Lymphopenia (including severely low and low ALC) was present in 53% of patients at MM diagnosis and was associated with inferior overall survival (OS). The median OS for patients with severely low, low, and normal ALC at diagnosis was 2.7, 3.3, and 4.2 years (P < .001), respectively. Moreover, persistent or new development of lymphopenia during treatment and follow-up was also associated with inferior OS. Our findings support the use of ALC as a biomarker for risk stratification in MM.

Tumor cells can drive the senescence of effector T cells by unbalancing their lipid metabolism, thereby limiting adoptive T cell therapy and contributing to tumor immune evasion. Our objective is to provide a feasible strategy for enhancing T cell treatment efficacy against solid tumors.

In this study, liposomal arachidonyl trifluoromethyl ketone (ATK) was anchored onto the adoptive T cell surface via bioorthogonal reactions, aiming to specifically inhibit the group IVA cytosolic phospholipase A2α (cPLA2α), a key enzyme facilitating phospholipid metabolism and senescent state of T cells.

The surface engineering exerted rare side effects on the activation and migration of T cells, but local and sustained extravasation of ATK downregulated cPLA2α expression, reprogrammed lipid metabolism, and inhibited lipid droplet accumulation. This endows T cells with delayed senescence and declined apoptosis to maintain their tumor-killing potency. Systemic administration of surface-engineered T cells resulted in superior infiltration in solid tumors and improved antitumor efficacy by enhancing the secretion of cytotoxic molecules, thereby prolonging the survival of mice bearing colorectal carcinoma and melanoma xenografts.

Lipid-metabolically remodeled T cells with delayed senescence increase efficacy in tumor microenvironment, highlighting a novel strategy for solid tumor immunotherapy.

Senescence is an inherent cellular mechanism triggered as a response to stressful insults. It associates with several aspects of cancer progression and therapy. Senescent cells constitute a highly heterogeneous cellular population and their identification can be very challenging. In fact, the term "senescence" has been often misused. This is also true in the case of immune cells. While several studies indicate the presence of senescent-like features (mainly in T cells), senescent immune cells are poorly described. Under this prism, we herein review the current literature on what has been characterized as T cell senescence and provide insights on how to accurately discriminate senescent cells against exhausted or anergic ones. We also summarize the major metabolic and epigenetic modifications associated with T cell senescence and underline the role of senescent T cells in the tumor microenvironment (TME). Moreover, we discuss how these cells associate with standard clinical therapeutic interventions and how they impact their efficacy. Finally, we underline the importance of precise identification and thorough characterization of "truly" senescent T cells in order to design successful therapeutic manipulations that would delay cancer incidence and maximize efficacy of immunotherapy.

Achieving sustained activity and tolerance in of allogeneic grafts after post-transplantation remains a substantial challenge. The response of the immune system to "non-self" MHC-antigenic peptides initiates a crucial phase, wherein blocking positive co-stimulatory signals becomes imperative to ensure graft survival and tolerance. MicroRNAs (miRNAs) inhibit mRNA translation or promote mRNA degradation by complementary binding of mRNA seed sequences, which ultimately affects protein synthesis. These miRNAs exhibit substantial promise as diagnostic, prognostic, and therapeutic candidates for within the realm of solid organ transplantations. Current research has highlighted three members of the T cell immunoglobulin and mucin domain (TIM) family as a novel therapeutic avenue in transplantation medicine and alloimmunization. The interplay between miRNAs and TIM proteins has been extensively explored in viral infections, inflammatory responses, and post-transplantation ischemia-reperfusion injuries. This review aims to elucidate the distinct roles of miRNAs and TIM in transplantation immunity and delineate their interdependent relationships in terms of targeted regulation. Specifically, this investigation sought seeks to uncover the potential of miRNA interaction with TIM, aiming to induce immune tolerance and bolster allograft survival after transplantation. This innovative strategy holds substantial promise in for the future of transplantation science and practice.

Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with the decrease and functional impairment of regulatory T cells (Tregs). In the current study, we explored the interplay of miR-155 and suppressor of cytokine signaling 1 (SOCS1) in regulating Treg function and stability in SLE.

Clinical samples from healthy subjects and SLE patients were collected, and a mouse model of SLE was established to profile the expression pattern of miR-155 and SCOS1 in Tregs. Tregs isolated from mouse spleen were stimulated by inflammatory cytokines to confirm involvement of miR-155/SOCS1 axis in dictating Treg stability and function. We also administrated synthetic miR-155 inhibitor in SLE animal model to evaluate the potential effect on rescuing Treg function and alleviating SLE progression.

Tregs from SLE patients and SLE-induced mice exhibited a downregulation of SOCS1 and an upregulation of miR-155. In Tregs stimulated by inflammatory cytokines, Nuclear factor kappa B (NF-κB) signaling activation was required for the change of SOCS1 and miR-155 expression. miR-155 served as a negative regulator to dampen SOCS1 expression in inflammation-stimulated Tregs. The transfection of miR-155 mimic impaired the suppressive function and differentiation of Tregs through targeting SOCS1. In contrast, miR-155 inhibition improved Treg function under inflammatory stimulation and alleviated SLE conditions in the mouse model.

Inflammation-induced miR-155 impairs Treg stability and function in SLE through decreasing SOCS1 expression. Targeting miR-155 might be developed as an intervention to mitigate SLE conditions.

While some literature has provided limited information about the potential cardiovascular risk and immune-related adverse events (irAEs) risk associated with PD-1/PD-L1 inhibitors in the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC), the exact relevance is still uncertain. To assess the pharmacovigilance (PV), constituent ratio, severity, and reaction outcomes of major adverse cardiovascular events (MACE) and immune-related adverse events (irAEs) related to PD-1/PD-L1 inhibitors for HNSCC reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed reports of cardiovascular adverse events and irAEs associated with drug therapy for HNSCC submitted to FAERS from the 1st quarter 2015 to the 3rd quarter of 2023. Three PD-1/PD-L1 inhibitors were identified: nivolumab, pembrolizumab and durvalumab. Our primary composite endpoint was the PV of MACE and irAEs related to PD-1/PD-L1 inhibitors in the treatment of HNSCC, and the secondary endpoint was PV of other cardiovascular events. The software implemented was STATA 17.0 MP. 19,372 suspected drug-adverse event reports related to drug treatment in patients with HNSCC were identified, of which 916 reports were cardiovascular events, including 555 reports of MACE and 361 reports of other cardiovascular events. The PV signal regarding MACE was detected in durvalumab (PRR  = 2.12, 95% CI: 1.24-3.61; χ2  = 7.71; ROR  = 2.19, 95% CI: 1.24-3.86; IC  = 1.01; IC025  = 0.07) but not in nivolumab and pembrolizumab. The constituent ratio of MACE in all adverse events caused by nivolumab (OR  = 0.38, 95% CI: 0.19-0.73) and pembrolizumab (OR  = 0.48, 95% CI: 0.23-0.99) was significantly decreased, compared with durvalumab. A PV signal about other cardiovascular events was detected in durvalumab (PRR  = 3.04, 95% CI: 1.73-5.31; χ2  = 16.13; ROR  = 3.15, 95% CI: 1.74-5.70; IC  = 1.46; IC025  = 0.48), but it was not detected in nivolumab or pembrolizumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR  = 0.25, 95% CI: 0.13-0.48) and pembrolizumab (OR  = 0.40, 95% CI: 0.20-0.80) was significantly decreased, compared with durvalumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR  = 0.61, 95% CI: 0.38-0.99) was significantly decreased, compared with pembrolizumab. There were 40 cases of hypertension. A PV signal about hypertension was detected in pembrolizumab (PRR  = 3.72, 95% CI: 1.87-7.43; χ2  = 15.99; ROR  = 3.75, 95% CI: 1.87-7.51; IC  = 1.53, IC025  = 0.45), but it was not detected in nivolumab. The constituent ratio of hypertension in all adverse events caused by nivolumab (OR  = 0.09, 95% CI: 0.09-0.39) was significantly decreased, compared with pembrolizumab. There were 737 cases of irAEs. A PV signal about irAEs was detected in nivolumab (PPR  = 1.27, 95% CI: 1.05-1.53; χ2  = 6.38; ROR  = 1.28, 95% CI: 1.06-1.56; IC  = 0.29, IC025  = -0.00) and pembrolizumab (PPR  = 2.20, 95% CI: 1.79-2.71; χ2  = 56.55; ROR  = 2.31, 95% CI: 1.84-2.88; IC  = 1.03; IC025  = 0.68), but it was not detected in durvalumab. The constituent ratio of irAEs in all adverse events caused by nivolumab (OR  = 0.58, 95% CI: 0.44-0.76) significantly decreased, compared with pembrolizumab. By comparing the PV signals, constituent ratio, severity, and reaction outcome of the three drugs, we suppose that nivolumab can be used as the safest PD-1/PD-L1 inhibitor for HNSCC.

Glioma is known for its immunosuppressive microenvironment, which makes it challenging to target through immunotherapies. Immune cells like macrophages, microglia, myeloid-derived suppressor cells, and T lymphocytes are known to infiltrate the glioma tumor microenvironment and regulate immune response distinctively. Among the variety of immune cells, T lymphocytes have highly complex and multifaceted roles in the glioma immune landscape. T lymphocytes, which include CD4+ helper and CD8+ cytotoxic T cells, are known for their pivotal roles in anti-tumor responses. However, these cells may behave differently in the highly dynamic glioma microenvironment, for example, via an immune invasion mechanism enforced by tumor cells. Therefore, T lymphocytes play dual roles in glioma immunity, firstly by their anti-tumor responses, and secondly by exploiting gliomas to promote immune invasion. As an immunosuppression strategy, glioma induces T-cell exhaustion and suppression of effector T cells by regulatory T cells (Tregs) or by altering their signaling pathways. Further, the expression of immune checkpoint inhibitors on the glioma cell surface leads to T cell anergy and dysfunction. Overall, this dynamic interplay between T lymphocytes and glioma is crucial for designing more effective immunotherapies. The current review provides detailed knowledge on the roles of T lymphocytes in the glioma immune microenvironment and helps to explore novel therapeutic approaches to reinvigorate T lymphocytes.

Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T-cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan-cancer scale. Thus, we aim to reveal its role at the pan-cancer level.

We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan-Meier survival analysis and multivariate Cox regression analysis. In pan-cancer analysis, we constructed competing endogenous RNA and protein-protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types.

LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43-17.90, P < 0.001) and PFS (HR = 3.44, 95% CI = 1.68-7.10, P < 0.001). In pan-cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune-related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers.

High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan-cancer dimension.

Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.

Lung cancer is a severe challenge to the health care system with intrinsic resistance to first and second-line chemo/radiotherapies. In view of the sterile environment of lung cancer, several immunotherapeutic drugs including nivolumab, pembrolizumab, atezolizumab, and durvalumab are currently being used in clinics globally with the intention of releasing exhausted T-cells back against refractory tumor cells. Immunotherapies have a limited response rate and may cause immune-related adverse events (irAEs) in some patients. Hence, a deeper understanding of regulating immune checkpoint interactions could significantly enhance lung cancer treatments. In this review, we explore the role of miRNAs in modulating immunogenic responses against tumors. We discuss various aspects of how manipulating these checkpoints can bias the immune system's response against lung cancer. Specifically, we examine how altering the miRNA profile can impact the activity of various immune checkpoint inhibitors, focusing on the PD-1/PD-L1 pathway within the complex landscape of lung cancer. We believe that a clear understanding of the host's miRNA profile can influence the efficacy of checkpoint inhibitors and significantly contribute to existing immunotherapies for lung cancer patients. Additionally, we discuss ongoing clinical trials involving immunotherapeutic drugs, both as standalone treatments and in combination with other therapies, intending to advance the development of immunotherapy for lung cancer.

Vigorous CD8+ T cells play a crucial role in recognizing tumor cells and combating solid tumors. How T cells efficiently recognize and target tumor antigens, and how they maintain the activity in the "rejection" of solid tumor microenvironment, are major concerns. Recent advances in understanding of the immunological trajectory and lifespan of CD8+ T cells have provided guidance for the design of more optimal anti-tumor immunotherapy regimens. Here, we review the newly discovered methods to enhance the function of CD8+ T cells against solid tumors, focusing on optimizing T cell receptor (TCR) expression, improving antigen recognition by engineered T cells, enhancing signal transduction of the TCR-CD3 complex, inducing the homing of polyclonal functional T cells to tumors, reversing T cell exhaustion under chronic antigen stimulation, and reprogramming the energy and metabolic pathways of T cells. We also discuss how to participate in the epigenetic changes of CD8+ T cells to regulate two key indicators of anti-tumor responses, namely effectiveness and persistence.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.

Patients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T cell receptor (TCR) β sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92 · 3% of patients received the primer vaccine, 70 · 8% received one monovalent booster, but only 30 · 1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR = 0 · 61, p = 0 · 024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed.