Neuromyotonia.

Neuromyotonia is continuous peripheral nerve hyper-excitability manifesting in muscle twitching at rest (myokymia), inducible cramps and impaired muscle relaxation, and characterized by EMG findings of spontaneous single motor unit discharges (with doublet, triplet, or multiplet morphology). The disorder may be genetic, acquired, and often in the acquired cases autoimmune. This chapter focuses on autoimmune acquired causes. Autoimmune associations include mainly contactin-associated protein-like 2 (CASPR2) antibody-associated disease (previously termed as VGKC or voltage-gated potassium channel antibody-associated neuromyotonia) (van Sonderen et al., 2016, p. 2), leucine-rich glioma-inactivated 1 (LGI1) antibody disease, the Guillain-Barré syndrome, NMDAR encephalitis (Varley et al., 2019), and IgLON5 (Gaig et al., 2021) disease. Nonimmune associations include radiation-induced plexopathy. An association with myasthenia gravis and other autoimmune disorders, response to plasma exchange (Newsom-Davis and Mills, 1993) and physiologically induced changes in mice injected with patient-derived immunoglobulins led to the discovery of autoantibodies to juxtaparanodal proteins complexed with potassium channels (Shillito et al., 1995). The target of the antibodies is most commonly the CASPR2 protein. The disorder may be paraneoplastic, and a search for and treatment of an underlying tumor is a necessary step. In cases in which there is evidence for an immune cause, then immune suppression, with an emerging role for B cell-depleting therapies, is associated with a good clinical outcome. In parallel, sodium channel blocking drugs remain effective symptomatic therapies.

Stemness, invasion, and immunosuppression modulation in recurrent glioblastoma using nanotherapy.

The recurrent nature of glioblastoma negatively impacts conventional treatment strategies leading to a growing need for nanomedicine. Nanotherapeutics, an approach designed to deliver drugs to specific sites, is experiencing rapid growth and gaining immense popularity. Having potential in reaching the hard-to-reach disease sites, this field has the potential to show high efficacy in combatting glioblastoma progression. The presence of glioblastoma stem cells (GSCs) is a major factor behind the poor prognosis of glioblastoma multiforme (GBM). Stemness potential, heterogeneity, and self-renewal capacity, are some of the properties that make GSCs invade across the distant regions of the brain. Despite advances in medical technology and MRI-guided maximal surgical resection, not all GSCs residing in the brain can be removed, leading to recurrent disease. The aggressiveness of GBM is often correlated with immune suppression, where the T-cells are unable to infiltrate the cancer initiating GSCs. Standard of care therapies, including surgery and chemotherapy in combination with radiation therapy, have failed to tackle all the challenges of the GSCs, making it increasingly important for researchers to develop strategies to tackle their growth and proliferation and reduce the recurrence of GBM. Here, we will focus on the advancements in the field of nanomedicine that has the potential to show positive impact in managing glioblastoma tumor microenvironment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Plasma Extracellular Vesicles Derived from Pediatric COVID-19 Patients Modulate Monocyte and T Cell Immune Responses Based on Disease Severity.

BACKGROUND: The COVID-19 pandemic has caused significant morbidity and mortality globally. The role of plasma-derived extracellular vesicles (EVs) in pediatric COVID-19 patients remains unclear. METHODS: We isolated EVs from healthy controls (n = 13) and pediatric COVID-19 patients (n = 104) with varying severity during acute and convalescent phases using serial ultracentrifugation. EV effects on healthy PBMCs, naïve CD4+ T cells, and monocytes were assessed through in vitro assays, flow cytometry, and ELISA. RESULTS: Our findings indicate that COVID-19 severity correlates with diverse immune responses. Severe acute cases exhibited increased cytokine levels, decreased IFNγ levels, and lower CD4+ T cell and monocyte counts, suggesting immunosuppression. EVs from severe acute patients stimulated healthy cells to express higher PDL1, increased Th2 and Treg cells, reduced IFNγ secretion, and altered Th1/Th17 ratios. Patient-derived EVs significantly reduced proinflammatory cytokine production by monocytes (p < .001 for mild, p = .0025 for severe cases) and decreased CD4+ T cell (p = .043) and monocyte (p = .033) populations in stimulated healthy PBMCs. CONCLUSION: This study reveals the complex relationship between immunological responses and EV-mediated effects, emphasizing the impact of COVID-19 severity. We highlight the potential role of plasma-derived EVs in early-stage immunosuppression in severe COVID-19 patients.

Quantifying the long-term effects of measles infection - A retrospective cohort study.

OBJECTIVE: To assess whether measles infection has an impact on the rate of non-measles infectious diseases over an extended period. METHODS: This retrospective matched cohort study included 532 measles diagnosed patients which were exactly matched with 2,128 individuals with no previous measles diagnosis. Adjusted Odds ratio for any all - cause infectious diagnosis and any viral infection diagnosis, up to 2 years post measles diagnosis, between the measles and control groups was obtained from a conditional logistic regression model. Cox proportional hazards model was employed to estimate the hazard ratio. RESULTS: - Previous measles (MeV) exposure was associated with an increased risk for all-cause non-measles infectious disease diagnosis (OR = 1.83, 95% CI 1.26-2.64, p = 0.001), with 492 diagnoses in the MeV-exposed group and 1868 diagnoses in the control group. Additionally, previous MeV exposure was linked to a higher risk of viral infection diagnosis (OR = 1.23, 95% CI 1.01-1.59, p < 0.05), with 302 viral infection diagnoses in the MeV-exposed group and 1107 diagnoses in the control group. The hazard ratio for viral diagnosis in the MeV-exposed group compared to the control group was 1.54 (95% CI 1.18-2.02, p < 0.001). CONCLUSION: Individuals diagnosed with measles had a moderate increased risk of being diagnosed with all cause non-measles infectious disease or viral infection. This observational individual level study supports previous ecological and individual population level studies.

Multi-Omics Analysis by Machine Learning Identified Lysophosphatidic Acid as a Biomarker and Therapeutic Target for Porcine Reproductive and Respiratory Syndrome.

As a significant infectious disease in livestock, porcine reproductive and respiratory syndrome (PRRS) imposes substantial economic losses on the swine industry. Identification of diagnostic markers and therapeutic targets has been a focal challenge in PPRS prevention and control. By integrating metabolomic and lipidomic serum analyses of clinical pig cohorts through a machine learning approach with in vivo and in vitro infection models, lysophosphatidic acid (LPA) is discovered as a serum metabolic biomarker for PRRS virus (PRRSV) clinical diagnosis. PRRSV promoted LPA synthesis by upregulating the autotaxin expression, which causes innate immunosuppression by dampening the retinoic acid-inducible gene I (RIG-I) and type I interferon responses, leading to enhanced virus replication. Targeting LPA demonstrated protection against virus infection and associated disease outcomes in infected pigs, indicating that LPA is a novel antiviral target against PRRSV. This study lays a foundation for clinical prevention and control of PRRSV infections.

Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.

Background: Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression. Methods: Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined. Results: Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response. Conclusions: Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.

Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodulatory functions in colorectal cancer and therapeutic implications.

OBJECTIVE: This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. METHODS: Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. RESULTS: CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. CONCLUSION: CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications.

Comparison of efficacy and safety of tofacitinib and azathioprine in patients with alopecia areata and variants: a double-blind, randomized controlled trial.

BACKGROUND: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair. OBJECTIVE: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants. METHODS: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study. RESULTS: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed. CONCLUSIONS: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants.

The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells.

BACKGROUND: Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape. MAIN BODY: In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions. CONCLUSION: We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.

Inflammation is a critical factor for successful regeneration of the adult zebrafish retina in response to diffuse light lesion.

Inflammation can lead to persistent and irreversible loss of retinal neurons and photoreceptors in mammalian vertebrates. In contrast, in the adult zebrafish brain, acute neural inflammation is both necessary and sufficient to stimulate regeneration of neurons. Here, we report on the critical, positive role of the immune system to support retina regeneration in adult zebrafish. After sterile ablation of photoreceptors by phototoxicity, we find rapid response of immune cells, especially monocytes/microglia and neutrophils, which returns to homeostatic levels within 14 days post lesion. Pharmacological or genetic impairment of the immune system results in a reduced Müller glia stem cell response, seen as decreased reactive proliferation, and a strikingly reduced number of regenerated cells from them, including photoreceptors. Conversely, injection of the immune stimulators flagellin, zymosan, or M-CSF into the vitreous of the eye, leads to a robust proliferation response and the upregulation of regeneration-associated marker genes in Müller glia. Our results suggest that neuroinflammation is a necessary and sufficient driver for retinal regeneration in the adult zebrafish retina.

An exploratory study of the efficacy and safety of amenamevir for the treatment of herpes zoster in patients receiving immunosuppressive drugs.

Amenamevir is an oral once-daily antiherpesvirus drug that can be administered without dose adjustment in patients with impaired renal function. There are currently no clinical data on immunocompromised patients with herpes zoster treated with amenamevir. Therefore, an exploratory study of the efficacy and safety of amenamevir against herpes zoster in patients with immunosuppression was conducted. Inclusion criteria included patients with acute herpes zoster receiving immunosuppressive drugs or those with malignant tumors or autoimmune diseases. Twenty-four patients were included and received amenamevir (400 mg once daily after meals) for up to 14 days. The primary end point of overall improvement in skin symptoms 7 days after treatment initiation (day 7) was 58.3% for "markedly improved" and 20.8% for "improved." The combined improvement rate was 79.2% (95% confidence interval, 57.8-92.9), and 20.8% of patients experienced "worsened" symptoms. The secondary end points of overall improvement in skin symptoms on day 14 and day 28 were 95.7% and 100%, respectively. The skin symptoms progressed during treatment, peaking on day 7, and then began to heal. By Kaplan-Meier estimation, the median periods to complete crusting and healing were both day 14. There were five adverse events with a possible causal relationship to amenamevir (bacterial skin infection, anemia, hyponatremia, headache, and abnormal liver function) in one of the 24 patients. Although the bacterial skin infection was severe, all events in this patient were reported to be either recovered or recovering. These findings indicate that amenamevir can be effective and safe in immunocompromised patients with herpes zoster. However, as worsening can happen around day 7, it is necessary to carefully monitor such patients and switch to other therapies such as intravenous acyclovir if necessary. Clinical trial identifier: Japan Registry of Clinical Trials jRCTs031190208.

Neuroimmune cell interactions and chronic infections in oral cancers.

Inflammation is a process that is associated with the activation of distal immunosuppressive pathways that have evolved to restore homeostasis and prevent excessive tissue destruction. However, long-term immunosuppression resulting from systemic and local inflammation that may stem from dysbiosis, infections, or aging poses a higher risk for cancers. Cancer incidence and progression dramatically increase with chronic infections including HIV infection. Thus, studies on pro-tumorigenic effects of microbial stimulants from resident microbiota and infections in the context of inflammation are needed and underway. Here, we discuss chronic infections and potential neuro-immune interactions that could establish immunomodulatory programs permissive for tumor growth and progression.

Modulation of cyclophosphamide-induced immunosuppression and intestinal flora in broiler by deep eutectic solvent extracted polysaccharides of Acanthopanax senticosus.

Introduction: The aim of this experiment was to investigate the modulation effect of Acanthopanax senticosus polysaccharide (ASPS-PD) extracted with deep eutectic solvent on cyclophosphamide-induced immunosuppression in broilers and its modulation of the gut microbiota of broilers. Methods: The 108 one-day-old broilers were divided into six groups, including the control group, the Cyclophosphamide (CY) model group, the ASPS-PD control group, the ASPA-PD high and low dose groups and the Astragalus polysaccharide group. Body weight, feed intake, feed conversion ratio, and immune organ index of broilers at 7, 14, and 21 days were determined; IL-2, IFN-γ, and lgG1 levels were determined by enzyme-linked immunosorbent assay (ELISA); Broiler caeca feces were analyzed by amplification and 16S rRNA sequencing. Results: The results showed that ASPS-PD can restore growth performance, increase immune organ index and improve serum cytokine levels of IL-2 and IFN-γ and immunoglobulin lgG1 levels in CY-treated broilers. The analysis of cecum flora showed that ASPS-PD can promote the proliferation of beneficial bacteria and reduce the number of harmful bacteria, regulating intestinal flora. Discussion: Therefore, ASPA-PD may be a potential novel immunomodulator to ameliorate CY-induced immunosuppression and intestinal flora dysregulation in broiler.

Immune Microenvironment in Childhood Cancers: Characteristics and Therapeutic Challenges.

The tumor immune microenvironment is pivotal in cancer initiation, advancement, and regulation. Its molecular and cellular composition is critical throughout the disease, as it can influence the balance between suppressive and cytotoxic immune responses within the tumor's vicinity. Studies on the tumor immune microenvironment have enriched our understanding of the intricate interplay between tumors and their immunological surroundings in various human cancers. These studies illuminate the role of significant components of the immune microenvironment, which have not been extensively explored in pediatric tumors before and may influence the responsiveness or resistance to therapeutic agents. Our deepening understanding of the pediatric tumor immune microenvironment is helping to overcome challenges related to the effectiveness of existing therapeutic strategies, including immunotherapies. Although in the early stages, targeted therapies that modulate the tumor immune microenvironment of pediatric solid tumors hold promise for improved outcomes. Focusing on various aspects of tumor immune biology in pediatric patients presents a therapeutic opportunity that could improve treatment outcomes. This review offers a comprehensive examination of recent literature concerning profiling the immune microenvironment in various pediatric tumors. It seeks to condense research findings on characterizing the immune microenvironment in pediatric tumors and its impact on tumor development, metastasis, and response to therapeutic modalities. It covers the immune microenvironment's role in tumor development, interactions with tumor cells, and its impact on the tumor's response to immunotherapy. The review also discusses challenges targeting the immune microenvironment for pediatric cancer therapies.

GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

A Single Centre Experience of Effective Desensitization Strategy for Children with High Anti-HLA Donor-Specific Antibodies Undergoing Haploidentical Hematopoietic Stem Cell Transplantation.

To assess the incidence of anti-HLA donor-specific antibodies and the effectiveness of desensitization strategy in children who underwent haploidentical HSCT at our hospital. A retrospective review, management and outcomes of children with positive anti-HLA DSA who underwent haploidentical HSCT at our hospital from 2020 to 2022. Three patients with Thalassemia major were treated with 2 cycles of pretransplant immune suppression (PTIS) comprising Fludarabine and Dexamethasone in addition to desensitization. Five out of the 26 children who underwent haploidentical HSCT had positive anti-HLA DSA. Post desensitization, three out of the 5 children engrafted with sustained full donor chimerism, 1 patient developed primary graft rejection, while 1 patient died. It is feasible to desensitize children with high anti-HLA donor specific antibodies undergoing haploidentical HSCT to improve outcomes.

Regulation of mouse digestive function, intestinal mucosal barrier function, and inflammatory reaction by lycium barbarum polysaccharide pathway through myosin light chain kinase.

This research investigated the impacts of lycium barbarum polysaccharide (LBP) on the digestive function, intestinal mucosal barrier function, inflammatory response, and myosin light chain kinase (MLCK) signaling pathway in immunosuppressed mice. 70 mg/kg cyclophosphamide was injected into abdomen for the preparation of immune suppression model. Healthy BALB/c mice served as control for the analysis of the differences in gastrointestinal motility and absorptive capacity, intestinal mucosal barrier function, the phagocytic ability of abdominal macrophages, serum immune factor and inflammatory factor levels, and the activation status of the MLCK signaling pathway after continuous gavage with 100 mg/kg LBP. Results revealed a decrease in d-xylose content, phagocytic rate, index of abdominal macrophages, and spleen index in the serum and urine of model mice compared to those of controls. In addition, levels of IgA, IgG, IgM, IL-6 (interleukin-6), IL-12, and interferon-γ (IFN-γ) decreased, while MLCK and myosin light chain (MLC) levels rose (P < 0.01). Versus those in Model group, urine d-xylose content, phagocytic rate, index of abdominal macrophages, spleen index, and the levels of IgA, IgG, IgM, IL-6, IL-12, and IFN-γ of mice undergoing the gavage with LBP increased, while MLCK and p-MLC levels declined (P < 0.05). In conclusion, LBP improved digestive absorption and immune function of immunosuppressed mice and regulated intestinal mucosal barrier immune system by inhibiting MLCK signaling pathway activation.

The multifaceted role of extracellular vesicles (EVs) in colorectal cancer: metastasis, immune suppression, therapy resistance, and autophagy crosstalk.

Extracellular vesicles (EVs) are lipid bilayer structures released by all cells and widely distributed in all biological fluids. EVs are implicated in diverse physiopathological processes by orchestrating cell-cell communication. Colorectal cancer (CRC) is one of the most common cancers worldwide, with metastasis being the leading cause of mortality in CRC patients. EVs contribute significantly to the advancement and spread of CRC by transferring their cargo, which includes lipids, proteins, RNAs, and DNAs, to neighboring or distant cells. Besides, they can serve as non-invasive diagnostic and prognostic biomarkers for early detection of CRC or be harnessed as effective carriers for delivering therapeutic agents. Autophagy is an essential cellular process that serves to remove damaged proteins and organelles by lysosomal degradation to maintain cellular homeostasis. Autophagy and EV release are coordinately activated in tumor cells and share common factors and regulatory mechanisms. Although the significance of autophagy and EVs in cancer is well established, the exact mechanism of their interplay in tumor development is obscure. This review focuses on examining the specific functions of EVs in various aspects of CRC, including progression, metastasis, immune regulation, and therapy resistance. Further, we overview emerging discoveries relevant to autophagy and EVs crosstalk in CRC.

Bioconjugated Antibody-Trojan Immune Converter Enhance Cancer Immunotherapy with Minimized Toxicity by Programmed Two-Step Immunomodulation of Myeloid Cells.

Current immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll-like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid-derived suppressor cells (MDSCs) and tumor-associated M2 macrophages, and boost dendritic cell (DC)-based T-cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two-step activation strategy via Antibody-Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti-SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody-mediated endocytosis. ATICC blocks the CD47-SIRPα ("don't eat me" signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs, and increases cross-presentation by DCs, resulting in antigen-specific CD8+ T-cell generation in tumor-draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen-specific CD8+ T cells, and antibody-dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities.

The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies.

Adenosine (Ado) is significantly elevated in the tumor microenvironment (TME) compared to normal tissues. It binds to adenosine receptors (AdoRs), suppressing tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors on dendritic cells (DCs) and macrophages, inhibiting antigen presentation. It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor (TCR) binding and signal transduction. Ado also inhibits chemokine secretion and KCa3.1 channel activity, impeding effector T cell trafficking and infiltration into the tumor site. Furthermore, Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion, upregulating immune checkpoint proteins, and enhancing immune-suppressive cell activity. Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies. Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.