Immune Inhibitors Research Articles

Current advancements in PD-L1 modulation by CMTM6 in malignant tumors

Abstract The CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6), a member of the chemokine-like factor superfamily, binds to programmed death-ligand 1 (PD-L1) on the cell membrane, thereby impeding PD-L1’s lysosomal degradation and sustaining its expression. In recent years, extensive studies on PD-L1 have provided insights into its function as an immunepoint inhibitor involved in tumor cell immune evasion. The specific interaction between CMTM6 and PD-L1 suggests a potential role in tumor cell immune evasion and suppression, potentially offering a novel therapeutic target for cancer immunotherapy. Currently, the research on CMTM6 and PD-L1 in diverse tumors and diseases is limited, but their significant roles are indicated. This article provides an overview of the impact of CMTM6 on the immune microenvironment in different types of cancer (such as lung cancer, breast cancer, and liver cancer), and summarizes the effects of CMTM6 on the occurrence and development of various tumors.

COMPREENDENDO A INTERSEÇÃO ENTRE HIV/AIDS E PNEUMONIA: UMA ANÁLISE ABRANGENTE DA LITERATURA

INTRODUCTION: The relationship between HIV/AIDS and pneumonia is complex and multifaceted. Individuals infected with HIV have a significantly higher risk of developing pneumonia, caused by both bacterial and viral agents, due to immune suppression from the virus. OBJECTIVE: To identify in the literature the relationship between HIV/AIDS and pneumonia in the context of nursing care. MATERIALS AND METHODS: This is an integrative literature review conducted in the MEDLINE, LILACS, and BDENF databases, using the descriptors: “HIV seropositivity,” “Pneumonia,” and “nursing care.” The descriptors were combined using the boolean operator AND, covering the period from 2018 to 2024. RESULTS: The study found that HIV-positive patients tend to experience a subacute progression of Pneumocystis jirovecii pneumonia (PCP), while immunocompromised patients without HIV face rapid progression, with a higher risk of respiratory failure and mortality. CT scans showed ground-glass opacities and elevated lactate dehydrogenase levels. Non-HIV patients had longer treatment delays and higher hospitalization and mortality rates. Lymphopenia, steroid use, and pneumothorax were associated with 60-day mortality. The incidence of bacterial pneumonia in people living with HIV decreased, linked to improved CD4 counts. Children with HIV showed higher mortality from coronavirus-related pneumonia. CONCLUSIONS: Future research should expand epidemiological surveillance, explore new therapies, and investigate co-infections in at-risk groups, particularly children. Additionally, strengthening public health policies and promoting prevention education are essential to improve clinical outcomes in vulnerable populations.

The diagnostic value of cytokines in chronic glomerulonephritis in children

In modern clinical practice of pediatricians, the problem of timely adequate treatment of chronic glomerulonephritis (CGN) in children is of particular relevance, due to both the high prevalence of the disease and the severity of its course, the complexity of therapy and the ambiguity of the prognosis. Lesions of the urinary system in children are not only common, but also tend to grow, and often at an early age. Deterioration of the environmental background, toxic and allergic effects of drugs lead to damage primarily to the kidneys, which are the eliminating organ. The aim of the study was to study urocytokines to assess the immune response in children with HCG, depending on the association with cytomegalovirus infection. The study included 100 children aged 4-7 years, permanently residing in the Bukhara region of the Republic of Uzbekistan. At the time of the study, the patients were undergoing routine treatment in the Department of Pediatric Nephrology of the Bukhara Regional Children’s Multidisciplinary Medical Center. All children underwent general clinical (general blood test with leukoformula, general urine analysis, biochemical blood test with determination of urea, creatinine and cystatin C, immunological (TNFα, IL-18, MCP-1, IgM and IgG antibodies to cytomegalovirus infection (CMVI) in blood serum, IL-1β and IL-17A in urine) examination methods. Thus, it was found that the concentration of cystatin C in the blood serum was inversely proportional to the glomerular filtration rate in the kidneys – with a decrease in kidney function in sick children, a twofold increase was noted, that is, the accumulation of cystatin C in the blood. An increase in the concentration of IL-18 in serum and IL-1β in urine relative to the control group in CGN was an indicator of the severity of an autoimmune reaction, and a relatively low concentration of cytokines in both blood and urine in CGN with CMVI indicated suppression of the specific antiviral immunity of CMVI. It was found that an increase in serum MCP-1 by 1.4 times in group 1 and 2.9 times in group 2 of CGN with CMVI is an indicator of viral kidney damage. A significantly high concentration of IL-17A in urine in CGN with CMVI indicated local cytokine production in the kidneys and acted as an indicator of the prognosis of the outcome of CGN.

Some parameters of the immune system in women with hyperandrogenism

The article is dedicated to studying certain parameters of the immune system, which holds great significance in obstetrics and gynecology. Examining immune system parameters allows for identifying disruptions in reproductive-aged women with hyperandrogenism, which holds crucial practical implications. The authors conducted an immunological study of women with hyperandrogenism and women without this pathology. The aim of the study was to investigate the immune system status in women suffering from hyperandrogenism. Materials and methods of the study: 58 reproductive-aged women diagnosed with hyperandrogenism, under observation at the Women’s Health Center “AyolCare” in Tashkent, were examined. Comprehensive clinical and laboratory examinations were conducted for all women. The control group comprised 35 practically healthy reproductive-aged women. The obtained results indicate that women with altered hormonal balance, including those with hyperandrogenism, experience specific changes in the immune system. The conducted research revealed that the levels of T lymphocytes and T helper/inducer cells decrease, while the number of T killer cells, CD25+ cells (carrying IL-2 receptor), and CD95+ cells (carrying apoptosis signaling receptor) increases. The elevated levels of CD95+ cells indicate increased activation of apoptosis processes, which serve as a protective function of T killer cells. This increase in lymphocyte activation is likely associated with elevated levels of mature activated macrophages and a range of cytokines they produce, which directly stimulate lymphocytes. The detected imbalance in immunological parameters likely indicates that in hyperandrogenism, either the elimination of activated clones of T helper cells is absent or disrupted, which usually leads to the formation of immune response suppression. The increase in the number of activated clones of T lymphocytes is observed in the decreased process of their apoptosis, which is likely intensified by the influence of androgens.

High PD-1 and CTLA-4 expression correlates with host immune suppression in patients and a mouse model infected with Echinococcus multilocularis

BackgroundAlveolar echinococcosis (AE), a fatal disease caused by Echinococcus multilocularis, often affects the liver, with tumor-like growth. However, the mechanism by which E. multilocularis evades host immune surveillance remains unclear.MethodsWe collected liver specimens from hepatic alveolar echinococcosis (HAE) patients and established a mouse model of E. multilocularis infection. Immunofluorescence staining and flow cytometry were performed to analyze programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4) expression in human samples, while flow cytometry and quantitative real-time polymerase chain reaction (PCR) were performed for similar analyses in mouse samples. Cell proliferation and protoscolex (PSC) killing assays were designed to explore how E. multilocularis induces host immunosuppression.ResultsAn inflammatory reaction band with high PD-1 and CTLA-4 expression was found in close liver tissue (CLT). The ratio of regulatory T cells (Tregs) was higher in CLT than in distant liver tissue (DLT), and Tregs in CLT tended to express higher levels of PD-1 and CTLA-4 than those in DLT from HAE patients. Echinococcus multilocularis-infected mice showed significantly elevated expression of PD-1 and CTLA-4 on splenocytes and peritoneal cells. PD-1/PD-L1 or CTLA-4 pathway blockade could relieve the immunosuppressive effects of Tregs from infected mice and enhance PSC killing by mouse splenocytes.ConclusionsE. multilocularis regulated the function of T cells via the PD-1/PD-L1- and CTLA-4-dependent pathways and subsequently evaded host immune attacks. These findings provide insights for investigating the pathogenic mechanism of AE.Graphical

Investigating the effect of synbiotic supplementation on inflammatory indices in critically ill septic children: a protocol study for randomized control trial

BackgroundSepsis, a severe inflammatory response to infection, is a global health priority due to its high mortality and long-term disability rates. Its pathophysiology involves both inflammation and immune suppression. Managing sepsis requires significant healthcare resources and expenditure, with sepsis being a leading cause of hospital costs. Gut microbiotas play a crucial role in sepsis, and probiotics show promise in managing it by restoring microbial balance. Despite advances, targeted therapies for sepsis remain elusive, necessitating innovative approaches such as probiotic therapy.MethodFifty-four eligible patients with sepsis will be randomly assigned to either the synbiotic or placebo group. The synbiotic supplement, KidiLact, comprises ten probiotic strains and prebiotic fructooligosaccharides. Participants will receive two sachets daily for 7 days, mixed with sterile water and administered orally or via gavage. Inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) will be evaluated. Anthropometric measurements, nutritional assessment, biochemical analysis, and clinical evaluation will be conducted to assess treatment outcomes. Statistical analysis will be performed to compare results between the two groups, employing SPSS version 19 with a significance level of P < .05.ConclusionThis randomized clinical trial aims to evaluate synbiotic supplementation effects on inflammatory markers and clinical outcomes in pediatric sepsis patients in the pediatric intensive care unit (PICU). Probiotics have shown promise in reducing proinflammatory cytokines like IL-6, TNF-α, and CRP, which are vital in the inflammatory response. Synbiotics can enhance gut integrity, preventing pathogen translocation and reducing inflammation. If our expectations regarding the effects of probiotics are correct, we can use them as a cost-effective supplement to improve the condition of pediatric sepsis in hospitals.Trial registrationIRCT,IRCT20230523058266N1 Registered 30 October 2023, https://irct.behdasht.gov.ir/trial/71397.

Hematological Cancer and Viral Infection

Hematological cancer patients are particularly vulnerable to the morbidity and death caused by viral infections. But, it is not well known how common viral infections are or what effects they have on patients undergoing traditional nontransplant treatment. How severe and how long T-cell-mediated immune suppression is determines the variation in viral infection incidence and prognosis between patient groups. Topics covered in this mini-review article include late CMV infection, new viral pathogens (human herpesvirus-6, BK virus, adenovirus, and human metapneumovirus), advancements in molecular diagnostics, and the possibility of novel agents for viral prophylaxis (maribavir) or preemptive therapy (valganciclovir). The infections caused by these viruses have been extensively studied. If we want to understand the range of these viral diseases and come up with effective ways to prevent and cure them, we need well-designed prospective trials. Patients undergoing nontransplant treatment for hematological malignancies are at greater risk for viral infections; this is especially important given the rising use of drugs like alemtuzumab, which cause significant T-cell depletion.

Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages.

Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.

The impact of trauma relevant concentrations of prostaglandin E2 on the anti-microbial activity of the innate immune system.

The mechanisms underlying the state of systemic immune suppression that develops following major trauma are poorly understood. A post-injury increase in circulating levels of prostaglandin E2 (PGE2) has been proposed as a contributory factor, yet few studies have addressed how trauma influences PGE2 biology. Blood samples from 95 traumatically-injured patients (injury severity score ≥8) were collected across the pre-hospital (≤2 hours), acute (4-12 hours) and subacute (48-72 hours) post-injury settings. Alongside ex vivo assessments of lipopolysaccharide (LPS)-induced cytokine production by monocytes, neutrophil reactive oxygen species production and phagocytosis, serum concentrations of PGE2 and its scavenger albumin were measured, and the expression of enzymes and receptors involved in PGE2 synthesis and signalling analysed. Leukocytes from trauma patients were treated with cyclooxygenase (COX) inhibitors (indomethacin or NS-398), or the protein kinase A inhibitor H89, to determine whether injury-induced immune suppression could be reversed by targeting the PGE2 pathway. The effect that trauma relevant concentrations of PGE2 had on the anti-microbial functions of neutrophils, monocytes and monocyte-derived macrophages (MDMs) from healthy controls (HC) was examined, as was the effect of PGE2 on efferocytosis. To identify factors that may trigger PGE2 production post-trauma, leukocytes from HC were treated with mitochondrial-derived damage associated molecular patterns (mtDAMPs) and COX-2 expression and PGE2 generation measured. PGE2 concentrations peaked in blood samples acquired ≤2 hours post-injury and coincided with significantly reduced levels of albumin and impaired LPS-induced cytokine production by monocytes. Significantly higher COX-2 and phospholipase A2 expression was detected in neutrophils and/or peripheral blood mononuclear cells isolated from trauma patients. Treatment of patient leukocytes with indomethacin, NS-398 or H89 enhanced LPS-induced cytokine production and neutrophil extracellular trap generation. Exposure to physiological concentrations of PGE2 suppressed the anti-microbial activity of monocytes, neutrophils and MDMs of HC, but did not influence efferocytosis. In a formyl-peptide receptor-1 dependent manner, mtDAMP treatment significantly increased COX-2 protein expression in neutrophils and monocytes, which resulted in increased PGE2 production. Physiological concentrations of PGE2 suppress the anti-microbial activities of neutrophils, monocytes and MDMs. Targeting the PGE2 pathway could be a therapeutic approach by which to enhance innate immune function post-injury.

Immune exhaustion in ME/CFS and long COVID.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are debilitating multisystemic conditions sharing similarities in immune dysregulation and cellular signaling pathways contributing to the pathophysiology. In this study, immune exhaustion gene expression was investigated in participants with ME/CFS or long COVID concurrently. RNA was extracted from peripheral blood mononuclear cells isolated from participants with ME/CFS (n = 14), participants with long COVID (n = 15), and healthy controls (n = 18). Participants with ME/CFS were included according to Canadian Consensus Criteria. Participants with long COVID were eligible according to the case definition for "Post COVID-19 Condition" published by the World Health Organization. RNA was analyzed using the NanoString nCounter Immune Exhaustion gene expression panel. Differential gene expression analysis in ME/CFS revealed downregulated IFN signaling and immunoglobulin genes, and this suggested a state of immune suppression. Pathway analysis implicated dysregulated macrophage activation, cytokine production, and immunodeficiency signaling. Long COVID samples exhibited dysregulated expression of genes regarding antigen presentation, cytokine signaling, and immune activation. Differentially expressed genes were associated with antigen presentation, B cell development, macrophage activation, and cytokine signaling. This investigation elucidates the intricate role of both adaptive and innate immune dysregulation underlying ME/CFS and long COVID, emphasizing the potential importance of immune exhaustion in disease progression.

Torque teno virus: a potential marker of immune reconstitution in youths with vertically acquired HIV

Torque teno virus (TTV) viral load (VL), a component of the human virome, increases during immune suppression or dysregulation. This study aimed to explore TTV VL in youths living with vertically acquired HIV (YWVH) and its potential as an immunovirological marker. We performed an observational, retrospective study involving YWVH under antiretroviral treatment (ART) from the Spanish Cohort of HIV-infected children, adolescents, and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO), compared to HIV-negative healthy donors (HD). Plasma TTV VL was assessed by qPCR. T-cell phenotype was analysed on cryopreserved peripheral blood mononuclear cells by flow cytometry. Correlations with baseline CD4 and CD8 and long-term virological evolution were examined. A total of 57 YWVH were compared with 23 HD. YWVH had a median CD4 T-cells of 736 cells/mm3 [IQR: 574–906], a median of 17 years [IQR: 14–20.5] since ART initiation, and 65 months [IQR: 39–116] under HIV-RNA virological control. TTV VL was higher among YWVH and in males compared with females (p < 0.05). Among YWVH, TTV VL correlated with CD4 and CD8 counts and the CD4/CD8 ratio (p = 0.002; r = − 0.39, p = 0.037; r = 0.277, p = 0.005; r = − 0.37 respectively). TTV VL correlated with activation expression markers (HLA-DR+/CD38+) on CD4 (p = 0.007, r = 0.39) and the soluble proinflammatory cytokine IL-6 (p = 0.006, r = 0.38).

Blocking S100A9-signaling is detrimental to the initiation of anti-tumor immunity.

S100A9, a multifunctional protein mainly expressed by neutrophils and monocytes, poses an immunological paradox. In virus infections or sterile inflammation, it functions as an alarmin attracting innate immune cells, as well as mediating proinflammatory effects through TLR4 signaling. However, in cancer, S100A9 levels have been shown to associate with poor prognosis and lack of response to immunotherapy. Its expression by myeloid cells has been related to an immune suppressive phenotype, the so-called myeloid derived suppressor cells (MDSCs). Targeting S100A9 in cancer has therefore been proposed as a potential way to relieve myeloid-mediated immune suppression. Surprisingly, we found that blocking the extracellular TLR4 signaling from S100A9 using the inhibitor Paquinimod, resulted in increased tumor growth and a detrimental effect on anti-PD-L1 efficacy in the CT26 tumor model. This effect was caused by a reduction in the tumor immune infiltration to about half of untreated controls, and the reduction was made up of a 5-fold decrease in Ly6Chigh monocytic cells. The suppressive Ly6G+ myeloid cells compartment was not reduced by Paquinimod treatment, suggesting alternative mechanisms by which S100A9 contributes to myeloid-mediated suppression. Intratumoral injection of recombinant S100A9 early after mice inoculation with CT26 cells had an anti-tumor effect. These findings indicate an important yet understudied role of S100A9 as an alarmin and immune stimulatory signal in cancer settings, and highlight the potential to exploit such signals to promote beneficial anti-tumor responses.

UL16‑binding protein 1 is a significant prognostic and diagnostic marker for breast cancer.

The aim of the present study was to investigate the association between UL16 binding protein 1 (ULBP1) and the prognosis of patients with and immune cell infiltration in breast cancer (BRCA). The mRNA data of BRCA and immune-related genes were extracted from The Cancer Genome Atlas and were analyzed using bioinformatics tools. Subsequently, the results obtained by bioinformatics were validated through the collection of clinical patient data at the Zibo Central hospital (Zibo, China). The difference in the expression of the ULBP1 gene between BRCA tissues and normal precancerous tissues was analyzed, followed by validation using immunohistochemistry. By combining clinical data from patients with BRCA, the prognostic and diagnostic significance of the ULBP1 gene in patients with BRCA was analyzed. Gene enrichment analysis was conducted to gain insight into the molecular mechanisms underlying the regulatory role of ULBP1 in BRCA by analyzing its related functions and signaling pathways. Furthermore, single sample gene set enrichment analysis (ssGSEA) and Spearman's correlation analysis were performed to explore the correlation between ULBP1 as a target gene related with tumor immune cell infiltration. The data revealed that ULBP1 is a target gene associated with immunity and the prognosis of patients with BRCA. Patients with BRCA with a high expression of ULBP1 had a poorer prognosis. ULBP1 expression correlated with progesterone receptor expression, estrogen receptor expression and histological type in patients with BRCA; thus, it may serve as an independent predictor for the overall survival rate of patients. Functional enrichment analysis revealed a significant co-expression between ULBP1 and ULBP2, ULBP3, retinoic acid early transcript 1K, as well as a significant enrichment of pathways associated with carcinogenesis and immune suppression. ssGSEA and Spearman's correlation analysis demonstrated significant correlations between ULBP1 expression and tumor immune cells, as well as immune checkpoints. Overall, the present study demonstrated that ULBP1 was associated with BRCA immunity and might serve as a prognostic and diagnostic biomarker for patients with BRCA. In addition, it might also be a potential target for the immunotherapy of BRCA.

From inflammation to invasion: Neutrophils in cervical cancer pathogenesis

Cervical cancer, predominantly caused by high-risk human papillomavirus (HPV) infections, continues to be a major health challenge globally. Recent research has highlighted the significant role of neutrophils, a type of white blood cell integral to the immune system, in the pathogenesis of cervical cancer. This review examines the dualistic role of neutrophils in cervical cancer, emphasizing their contribution to both inflammation and tumor progression. Understanding the intricate relationship between neutrophils and cervical cancer could unveil new therapeutic targets for better disease management. Neutrophils are key mediators of the immune response and inflammation. In the context of cervical cancer, these cells are recruited to the tumor microenvironment where they can adopt tumor-promoting phenotypes. Tumor-associated neutrophils (TANs) facilitate various processes that aid tumor growth and metastasis, such as producing reactive oxygen species (ROS) and proteases that induce DNA damage, releasing cytokines and chemokines that promote angiogenesis, and forming neutrophil extracellular traps (NETs) that enhance metastatic potential. Furthermore, TANs contribute to immune suppression by inhibiting the activity of cytotoxic T lymphocytes and natural killer cells, allowing cancer cells to evade immune surveillance. Given their pivotal role in cervical cancer progression, neutrophils represent a promising target for novel therapeutic strategies. Approaches such as inhibiting neutrophil recruitment to the tumor site, blocking NET formation, and modulating TAN phenotypes from pro-tumor to anti-tumor are being explored. These strategies aim to disrupt the supportive role of neutrophils in tumor development and progression, potentially leading to improved outcomes for patients with cervical cancer.

The Utilization of PRAME in the Diagnosis, Prognosis, and Treatment of Melanoma.

Melanoma, a deadly form of skin cancer, has seen improved survival rates due to advances in diagnosis and treatment, yet the need for further improvement remains critical. Tumor-associated antigens, such as PRAME (Preferentially Expressed Antigen in Melanoma), offer promising avenues for enhanced diagnostic precision, prognostic assessment, and targeted immunotherapy. PRAME, a cancer testis antigen, is selectively expressed in various cancers, including melanoma, and plays a key role in promoting tumorigenesis through inhibition of retinoic acid signaling, epithelial-to-mesenchymal transition, and immune evasion. This review explores the diagnostic utility of PRAME in distinguishing melanoma from benign nevi, its prognostic value in aggressive melanoma subtypes, and its potential as a therapeutic target in cancer vaccines and adoptive T-cell therapies. While PRAME-targeted therapies face challenges such as tumor heterogeneity and immune suppression, ongoing research aims to overcome these barriers, offering hope for more effective melanoma treatments.

Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer.

Iron is an essential biomineral in the human body. Here, we describe a subset of iron-loaded cancer-associated fibroblasts, termed as FerroCAFs, that utilize iron to induce immunosuppression in prostate cancer and predict an unfavorable clinical outcome. FerroCAFs secrete myeloid cell-associated proteins, including CCL2, CSF1 and CXCL1, to recruit immunosuppressive myeloid cells. We report the presence of FerroCAFs in prostate cancer from both mice and human, as well as in human lung and ovarian cancers, and identify a conserved cell surface marker, the poliovirus receptor. Mechanistically, the accumulated iron in FerroCAFs is caused by Hmox1-mediated iron release from heme degradation. The intracellular iron activates the Kdm6b, an iron-dependent epigenetic enzyme, to induce an accessible chromatin state and transcription of myeloid cell-associated protein genes. Targeting the FerroCAFs by inhibiting the Hmox1/iron/Kdm6b signaling axis incurs anti-tumor immunity and tumor suppression. Collectively, we report an iron-loaded FerroCAF cluster that drives immunosuppression through an iron-dependent epigenetic reprogramming mechanism and reveal promising therapeutic targets to boost anti-tumor immunity.

Three-dimensional silk fibroin scaffolded co-culture of human neuroblastoma and innate immune cells

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. It accounts for 50 % of cancers diagnosed in infants less than 1 year old, and 10 % of all pediatric cancer deaths in the United States. High-risk patients have a less than 50 % 5-year survival rate with current treatment strategies. The complex tumor microenvironment of NB makes the development of treatment strategies for high-risk patients challenging. There is increasing evidence that intratumoral immune suppression plays an important role in the progression and invasion of NB tumors. Few three-dimensional (3D) cancer models include components of the innate immune system. This work develops a preclinical 3D NB-immune co-culture model using SK-N-AS NB cells, NK-92 natural killer cells, and THP-1 derived macrophages, co-cultured on porous 3D silk scaffolds to provide tumor architecture. Conditioned media and indirect co-culturing showed changes in SK-N-AS gene expression associated with immunoregulatory signaling, and changes in NK-92 gene expression that are associated with reduced cytotoxicity. This motivated the development of a 3D direct co-culture system in which NB cells were seeded prior to immune cells to allow incorporation and deposition of extracellular matrix within the construct. Immune cells were then incorporated into the model to achieve direct co-culture with SK-N-AS cells. Changes in THP-1 macrophage polarization toward a more M2-like phenotype were observed in 3D direct co-culture, as well as altered NK-92 cell protein secretion and cytotoxic activity. Preliminary testing of immunotherapeutics within the model was conducted on both NB-macrophage and NB-NK co-cultures, but the model demonstrated limited response to immunotherapeutics. This work lays the foundation for building high-throughput therapeutic screening models for the improved treatment NB and other solid tumors.

Activation of plant immunity through conversion of a helper NLR homodimer into a resistosome.

Nucleotide-binding domain and leucine-rich repeat (NLR) proteins can engage in complex interactions to detect pathogens and execute a robust immune response via downstream helper NLRs. However, the biochemical mechanisms of helper NLR activation by upstream sensor NLRs remain poorly understood. Here, we show that the coiled-coil helper NLR NRC2 from Nicotiana benthamiana accumulates in vivo as a homodimer that converts into a higher-order oligomer upon activation by its upstream virus disease resistance protein Rx. The cryo-EM structure of NbNRC2 in its resting state revealed intermolecular interactions that mediate homodimer formation and contribute to immune receptor autoinhibition. These dimerization interfaces have diverged between paralogous NRC proteins to insulate critical network nodes and enable redundant immune pathways, possibly to minimise undesired cross-activation and evade pathogen suppression of immunity. Our results expand the molecular mechanisms of NLR activation pointing to transition from homodimers to higher-order oligomeric resistosomes.

MAZ promotes tumor proliferation and immune evasion in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

Recent advancements in cGAS-STING activation, tumor immune evasion, and therapeutic implications.

The cGAS-STING signaling pathway is indeed a pivotal component of the immune system and serve as a crucial link between innate and adaptive immune responses. STING is involved in the cellular response to pathogen invasion and DNA damage, and which has important consequences for host defense mechanisms and cancer regulation. Ongoing research aiming to modulate the cGAS-STING pathway for improved clinical outcomes in cancer and autoimmune diseases is underway. Indeed, the interaction between the cGAS-STING pathway and immune evasion mechanisms is a complex and critical aspect of cancer biology. Pathogens and various host factors can exploit this pathway to reduce the effectiveness of cancer therapies, particularly immunotherapies. Thus, immunotherapies or combination therapies may assist in overcoming the immune suppression and improving clinical outcomes. This review explores recent advancements in understanding the cGAS-STING signaling pathway, with particular emphasis on its activation mechanisms and role in tumor immune evasion. The dual role of the pathway in boosting immune responses while simultaneously enabling tumors to evade the immune system makes it a crucial target for innovative cancer treatment approaches.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 2 Given name: [Md Mazedul] Last name [Islam], Author 3 Given name: [Mst Rubaiat Nazneen] Last name [Akhand] and Author 5 Given name: [Md Rashedunnabi] Last name [Akanda]. Also, kindly confirm the details in the metadata are correct.AQ1: Here Author 4 given name: [Byung-Yong] Last name [Park] is missing. Metadata are correct.