Immune System Interactions Research Articles

Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives

Implications of tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer: clinical oncologist perspectives

The Interaction of Immune System in Tumour Microenvironment and Possible Role of Cancer Cell Immnunosensitization for Better Treatment Efficacy: A Review

Unlike haematologic malignant cells which express cell surface common antigens uniformly and are susceptible to targeted cancer immunotherapy, solid tumours either lack such antigens or have been mutated due to chemotherapy or other therapeutic interventions. Moreover, rapidly dividing tumour cells present complex and dynamic tumour metabolism, which hampers immune cells' reactivity against the tumour cells. Hence solid tumours other than immune-sensitive cancers such as melanoma and renal cell carcinoma are less responsive towards current cellular immunotherapy strategies, including cytokine therapy, dendritic cell-based vaccines, and immune-activating antibodies. Nonetheless, emerging evidence supports combined approaches that target immunosuppressive or antiapoptotic molecules, involving sensitization of the cancer cells by immunosensitizing drugs to express specific ligands that will be recognized by the immune cells via trafficking. This review highlights the immune system's involvement in the tumour microenvironment and the potential significance of cancer cell immunosensitization for improved treatment outcomes.

Recent Advances in Assessing the Clinical Implications of Epstein-Barr Virus Infection and Their Application to the Diagnosis and Treatment of Nasopharyngeal Carcinoma.

Reports about the oncogenic mechanisms underlying nasopharyngeal carcinoma (NPC) have been accumulating since the discovery of Epstein-Barr virus (EBV) in NPC cells. EBV is the primary causative agent of NPC. EBV-host and tumor-immune system interactions underlie the unique representative pathology of NPC, which is an undifferentiated cancer cell with extensive lymphocyte infiltration. Recent advances in the understanding of immune evasion and checkpoints have changed the treatment of NPC in clinical settings. The main EBV genes involved in NPC are LMP1, which is the primary EBV oncogene, and BZLF1, which induces the lytic phase of EBV. These two multifunctional genes affect host cell behavior, including the tumor-immune microenvironment and EBV behavior. Latent infections, elevated concentrations of the anti-EBV antibody and plasma EBV DNA have been used as biomarkers of EBV-associated NPC. The massive infiltration of lymphocytes in the stroma suggests the immunogenic characteristics of NPC as a virus-infected tumor and, at the same time, also indicates the presence of a sophisticated immunosuppressive system within NPC tumors. In fact, immune checkpoint inhibitors have shown promise in improving the prognosis of NPC patients with recurrent and metastatic disease. However, patients with advanced NPC still require invasive treatments. Therefore, there is a pressing need to develop an effective screening system for early-stage detection of NPC in patients. Various modalities, such as nasopharyngeal cytology, cell-free DNA methylation, and deep learning-assisted nasopharyngeal endoscopy for screening and diagnosis, have been introduced. Each modality has its advantages and disadvantages. A reciprocal combination of these modalities will improve screening and early diagnosis of NPC.

Ash1L ameliorates psoriasis via limiting neuronal activity-dependent release of miR-let-7b.

Psoriasis is a common autoimmune skin disease that significantly diminishes patients' quality of life. Interactions between primary afferents of the somatosensory system and the cutaneous immune system mediate the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanisms of how primary sensory neurons regulate psoriasis formation. Skin and total RNA were extracted from wild-type (WT) and ASH1-like histone lysine methyltransferase (Ash1l+/- ) mice in both naive and imiquimod (IMQ)-induced psoriasis models. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence-activated cell sorting (FACS) were then performed. Microfluidic chamber coculture was used to investigate the interaction between somatosensory neurons and bone marrow dendritic cells (BMDCs) ex vivo. Whole-cell patch clamp recordings were used to evaluate neuronal excitability after Ash1L haploinsufficiency in primary sensory neurons. The haploinsufficiency of ASH1L, a histone methyltransferase, in primary sensory neurons causes both neurite hyperinnervation and increased neuronal excitability, which promote miR-let-7b release from primary afferents in the skin in a neuronal activity-dependent manner. With a 'GUUGUGU' core sequence, miR-let-7b functions as an endogenous ligand of toll-like receptor 7 (TLR7) and stimulates the activation of dermal dendritic cells (DCs) and interleukin (IL)-23/IL-17 axis, ultimately exacerbating the symptoms of psoriasis. Thus, by limiting miR-let-7b release from primary afferents, ASH1L prevents dermal DC activation and ameliorates psoriasis. Somatosensory neuron ASH1L modulates the cutaneous immune system by limiting neuronal activity-dependent release of miR-let-7b, which can directly activate dermal DCs via TLR7 and ultimately lead to aggravated psoriatic lesion.

Brain-Splenic Immune System Interactions in Hypertension: Cellular and Molecular Mechanisms.

Hypertension represents a major worldwide cause of death and disability, and it is becoming increasingly clear that available therapies are not sufficient to reduce the risk of major cardiovascular events. Various mechanisms contribute to blood pressure increase: neurohormonal activation, autonomic nervous system imbalance, and immune activation. Of note, the brain is an important regulator of blood pressure levels; it recognizes the peripheral perturbation and organizes a reflex response by modulating immune system and hormonal release to attempt at restoring the homeostasis. The connection between the brain and peripheral organs is mediated by the autonomic nervous system, which also modulates immune and inflammatory responses. Interestingly, an increased autonomic nervous system activity has been correlated with an altered immune response in cardiovascular diseases. The spleen is the largest immune organ exerting a potent influence on the cardiovascular system during disease and is characterized by a dense noradrenergic innervation. Taken together, these aspects led to hypothesize a key role of neuroimmune mechanisms in the onset and progression of hypertension. This review discusses how the nervous and splenic immune systems interact and how the mechanisms underlying the neuroimmune cross talk influence the disease progression.

From heart to gut: Exploring the gut microbiome in congenital heart disease.

Congenital heart disease (CHD) is a prevalent birth defect and a significant contributor to childhood mortality. The major characteristics of CHD include cardiovascular malformations and hemodynamical disorders. However, the impact of CHD extends beyond the circulatory system. Evidence has identified dysbiosis of the gut microbiome in patients with CHD. Chronic hypoxia and inflammation associated with CHD affect the gut microbiome, leading to alterations in its number, abundance, and composition. The gut microbiome, aside from providing essential nutrients, engages in direct interactions with the host immune system and indirect interactions via metabolites. The abnormal gut microbiome or its products can translocate into the bloodstream through an impaired gut barrier, leading to an inflammatory state. Metabolites of the gut microbiome, such as short-chain fatty acids and trimethylamine N-oxide, also play important roles in the development, treatment, and prognosis of CHD. This review discusses the role of the gut microbiome in immunity, gut barrier, neurodevelopment, and perioperative period in CHD. By fostering a better understanding of the cross-talk between CHD and the gut microbiome, this review aims to contribute to improve clinical management and outcomes for CHD patients.

Construction and validation of a immune-related prognostic gene DHRS1 in hepatocellular carcinoma based on bioinformatic analysis.

A member of the short-chain dehydrogenase/reductase superfamily (DHRS1, SDR19C1) is a member of the short-chain dehydrogenase/reductase superfamily and a potential predictor of hepatocellular carcinoma (HCC). However, the role of DHRS1 in HCC immunity remains unclear. We systematically analyzed the association between DHRS1 and HCC immunity with transcriptional and clinical data from the Tumor Immune Estimation Resource, an integrated repository portal for tumor immune system interactions, and cBioPortal databases. Six DHRS1-associated immunomodulators strongly correlated with survival and were uncovered by exploiting univariate and multivariate Cox analyses. We created a risk score for each patient by adding the points from each immunomodulator and then classified them into high and low risk categories. Survival analysis were used to compare the overall survival between the 2 groups, and the receiver operating characteristic curve was applied to assess the accuracy of the risk score. Data from our center were adopted as the external validation set, the risk score was calculated using the risk coefficient of the 6 genes in the training cohort, and survival analysis were executed to verify the experimental group results. A nomogram was ultimately constructed with the R package. Our data revealed a correlation between the levels of immune cell infiltration and either the DHRS1 gene copy numbers or mRNA levels in HCC. Second, we generated a signature based on the 6 DHRS1-related immunomodulators (KDR, TNFRSF4, CD276, TNFSF4, SLAMF6, and SIGLEC9). We postulate that the generated risk scores would serve as an independent indicator of HCC prognosis, with an area under the receiver operating characteristic curve for the risk score of 0.743. We further established external validation sets to reconfirm the predictive validity of the risk score. Finally, a prognostic nomogram and calibration curve were created. The DHRS1 gene may exert an impact on HCC immunity. We posit that the nominated immune signature based on DHRS1-associated immunomodulators could constitute a promising prognostic biomarker in HCC.

Pregnancy by Oocyte Donation: Reviewing Fetal-Maternal Risks and Complications.

Oocyte donation (OD) has greatly improved over the last three decades, becoming a preferred practice of assisted reproductive technology (ART) for infertile women wishing for motherhood. Through OD, indeed, it has become possible to overcome the physiological limitation due to the ovarian reserve (OR) exhaustion as well as the poor gamete reliability which parallels the increasing age of women. However, despite the great scientific contribution related to the success of OD in the field of infertility, this practice seems to be associated with a higher rate of major risky events during pregnancy as recurrent miscarriage, infections and placental diseases including gestational hypertension, pre-eclampsia and post-partum hemorrhage, as well as several maternal-fetal complications due to gametes manipulation and immune system interaction. Here, we will revisit this questioned topic since a number of studies in the medical literature focus on the successful aspects of the OD procedure in terms of pregnancy rate without, however, neglecting the risks and complications potentially linked to external manipulation or heterologous implantation.

Unravelling the potential of susceptibility genes in plant disease management: Present status and future prospects

The increasing global population requires an equivalent increase in food production to meet the global food demand. Crop production is challenged by various biotic and abiotic stresses, which decrease crop yield and production. Thus, proper disease management for crops ensures global food security. Various chemical, physical, and biological disease control methods have been devised and used for plant protection. However, due to the low efficiency of these methods, modern research has shifted to genetic engineering approaches. The recent advances in molecular techniques have revealed the molecular mechanisms controlling the plant’s innate immune system and plant-pathogen interactions. Earlier studies revealed that the pathogens utilize the susceptibility (S) genes in hosts for their sustainability and disease development. The resistance achieved by suppressing the S genes expression provides resistance against pathogens. Exploiting S genes for imparting/enhancing disease resistance would offer a more durable and effective alternative to conventional disease control methods. Therefore, the present review highlights the potential of this novel tool for inducing disease resistance in plants.

A Fractional Perspective on the Dynamics of HIV, Considering the Interaction of Viruses and Immune System with the Effect of Antiretroviral Therapy

HIV infection is a worldwide health threat, necessitating a multifaceted strategy that includes prevention, testing, treatment and care. Moreover, it is essential to address the structural and social factors that influence the spread of this viral infection. In this study, we utilize fractional calculus to clarify the dynamics of HIV infection in vivo, specifically examining the interface amid the HIV and the immune system and taking into account the impact of antiretroviral therapy. We use important results from fractional theory to analyze our proposed model of HIV infection and developed a numerical scheme to depict the system’s dynamic behavior. By varying input factors, we were able to observe the system’s chaotic nature and track its trajectory, as well as examine the effect of viruses on T-cells. Our results reveal key factors affecting the system, and demonstrate the consequence of antiretroviral therapy on our proposed model of HIV. Moreover, we observe that the system’s strong non-linearity is responsible for the oscillation phenomena and identify the most sensitive parameters of the system.

MYC Promotes Aggressive Growth and Metastasis of a WNT-Medulloblastoma Mouse Model

Medulloblastoma (MB), the most common malignant pediatric brain tumor, comprises four molecularly and clinically distinct subgroups (termed WNT, SHH, group 3, and group 4). Prognosis varies based on genetic and pathological features associated with each molecular subgroup. WNT-MB, considered low-risk, is rarely metastatic and contains activating mutations in CTNNB1; group 3-MB (GRP3-MB), commonly classified as high-risk, is frequently metastatic and can contain genomic alterations, resulting in elevated MYC expression. Here, we compare model systems of low-risk WNT-MB and high-risk GRP3-MB to identify tumor and microenvironment interactions that could contribute to features associated with prognosis. Compared to GRP3-MB, we find that WNT-MB is enriched in gene sets related to extracellular matrix (ECM) regulation and cellular adhesion. Exogenous expression of MycT58A in a murine WNT-MB model significantly accelerates growth and results in metastatic disease. In addition to decreased ECM regulation and cell adhesion pathways, we also identified immune system interactions among the top downregulated signaling pathways following MycT58A expression. Taken together, our data provide evidence that increased Myc signaling can promote the growth and metastasis in a murine model of WNT-MB.

Peptide Hydrogels as Immunomaterials and Their Use in Cancer Immunotherapy Delivery.

Peptide-based hydrogel biomaterials have emerged as an excellent strategy for immune system modulation. Peptide-based hydrogels are supramolecular materials that self-assemble into various nanostructures through various interactive forces (i.e., hydrogen bonding and hydrophobic interactions) and respond to microenvironmental stimuli (i.e., pH, temperature). While they have been reported in numerous biomedical applications, they have recently been deemed promising candidates to improve the efficacy of cancer immunotherapies and treatments. Immunotherapies seek to harness the body's immune system to preemptively protect against and treat various diseases, such as cancer. However, their low efficacy rates result in limited patient responses to treatment. Here, the immunomaterial's potential to improve these efficacy rates by either functioning as immune stimulators through direct immune system interactions and/or delivering a range of immune agents is highlighted. The chemical and physical properties of these peptide-based materials that lead to immuno modulation and how one may design a system to achieve desired immune responses in a controllable manner are discussed. Works in the literature that reports peptide hydrogels as adjuvant systems and for the delivery of immunotherapies are highlighted. Finally, the future trends and possible developments based on peptide hydrogels for cancer immunotherapy applications are discussed.

Improving the safety and efficacy of phage therapy from the perspective of phage-mammal interactions.

Phage therapy has re-emerged as a promising solution for combating antimicrobial-resistant bacterial infections. Increasingly, studies have revealed that phages possess therapeutic potential beyond their antimicrobial properties, including regulating the gut microbiome and maintain intestinal homeostasis, as a novel nanocarrier for targeted drug delivery. However, the complexity and unpredictability of phage behavior during treatment pose a significant challenge in clinical practice. The intricate interactions established between phages, humans, and bacteria throughout their long coexistence in the natural ecosystem contribute to the complexity of phage behavior in therapy, raising concerns about their efficacy and safety as therapeutic agents. Revealing the mechanisms by which phages interact with the human body will provide a theoretical basis for increased application of promising phage therapy. In this review, we provide a comprehensive summary of phage-mammal interactions, including signaling pathways, adaptive immunity responses, and phage-mediated anti-inflammatory responses. Then, from the perspective of phage-mammalian immune system interactions, we present the first systematic overview of the factors affecting phage therapy, such as the mode of administration, the physiological status of the patient, and the biological properties of the phage, to offer new insights into phage therapy for various human diseases.

Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction.

Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction.

Transcriptome profiling and differential expression analysis of altered immune-related genes in goldfish (Carassius auratus) infected with Aeromonas hydrophila

Goldfish (Carassius auratus) have been employed as a model organism to investigate the innate immune system and host-pathogen interactions. A Gram-negative bacterium called Aeromonas hydrophila has been found to cause mass mortality due to infection in a wide variety of fish species in the aquatic system. In this study, damages in Bowman's capsule, inflammatory tubular (proximal and distilled convoluted) structure, and glomerular necrosis were observed in A. hydrophila-infected head kidney of goldfish. To increase the better understanding of immune mechanisms of host defense against A. hydrophila, we performed a transcriptome analysis in head kidney of goldfish at 3 and 7 days of post-infection (dpi). Comparing to the control group, 4638 and 2580 differentially expressed genes (DEGs) were observed at 3 and 7 dpi, respectively. The DEGs were subsequently enriched in multiple immune-related pathways including Protein processing in endoplasmic reticulum, Insulin signaling pathway, and NOD-like receptor signaling pathway. The expression profile of immune-related genes such as TRAIL, CCL19, VDJ recombination-activating protein 1-like, Rag-1, and STING was validated by qRT-PCR. Furthermore, the levels of immune-related enzyme (LZM, AKP, SOD, and CAT) activities were examined at 3 and 7 dpi. The knowledge gained from the current study will be helpful for better understanding of early immune response in goldfish after A. hydrophila challenge, which will aid in future research on prevention strategies in teleost.

In Vivo HIV Dynamics, Modeling the Interaction of HIV and Immune System via Non-Integer Derivatives

The economic burden of HIV extends beyond the individual level and affects communities and countries. HIV can lead to decreased economic growth due to lost productivity and increased healthcare costs. In some countries, the HIV epidemic has led to a reduction in life expectancy, which can impact the overall quality of life and economic prosperity. Therefore, it is significant to investigate the intricate dynamics of this viral infection to know how the virus interacts with the immune system. In the current research, we will formulate the dynamics of HIV infection in the host body to conceptualize the interaction of T-cells and the immune system. The recommended model of HIV infection is presented with the help of fractional calculus for more precious outcomes. We introduce numerical methods to demonstrate how the input parameters affect the output of the system. The dynamical behavior and chaotic nature of the system are visualized with the variation of different input factors. The system’s tracking path has been numerically depicted and the impact of the viruses on T-cells has been demonstrated. In addition to this, the key factors of the system has been predicted through numerical findings. Our results predict that the strong non-linearity of the system is responsible for the chaos and oscillation, which are so closely related. The chaotic parameters of the system are highlighted and are recommended for the control of the chaos of the system.

Simple and easily accessible prognostic markers in ewing sarcoma; neutrophil-lymphocyte ratio, neutrophil-platelet score and systemic-inflammation index.

Inflammation markers are the new point of view in cancer due to increasing data on the interaction of immune system with tumor cells and their prognostic and predictive importance were found in many different types of solid tumors. Therefore, we aimed to evaluate the prognostic value of neutrophil-lymphocyte ratio (NLR), neutrophil-platelet score (NPS), and systemic inflammation index (SII) in Ewing sarcoma patients in which risk groups are still not clearly defined. A total of 64 patients were evaluated retrospectively. Receiver operating characteristic analysis was performed to find cut-off values for NLR and SII. Survival analysis was calculated by using Kaplan-Meier method. Cox regression analysis was performed to determine prognostic factors such as age, stage, and neoadjuvant chemotherapy were statistically significant prognostic factors for OS in multivariate analysis. While patients with low NLR and SII had longer OS (P = 0.003 and P = 0.018), patients with high NPS score had shorter OS (67.7 vs 21.7 months, P = 0.001). Patients with lower NLR, NPS, and SII score have a better prognosis compared with those with higher NLR, NPS, and SII score and these simple parameters may be monitoring tools of the tumor microenvironment.

The immunomodulatory effect of IL-4 accelerates bone substitute material-mediated osteogenesis in aged rats via NLRP3 inflammasome inhibition.

Bone defect repair by implanting bone substitute materials has been a common clinical treatment. With the understanding of substance-immune system interactions and increasing evidence indicating that the post-implantation immune response determines the fate of bone substitute materials, active modulation of host macrophage polarization is considered a promising strategy. However, whether the same regulatory effects exist when an individual immune system is altered with aging is unclear. In this study, we mechanistically investigated the effect of immunosenescence on the active regulation of macrophage polarization by establishing a cranial bone defect model in young and aged rats implanted with Bio-Oss®. Forty-eight young and 48 aged specific pathogen-free (SPF) male SD rats were randomly divided into two groups. In the experimental group, 20 μL of IL-4 (0.5 μg/mL) was injected locally on the third to seventh postoperative days, while an equal volume of PBS was injected in the control group. Specimens were collected at 1, 2, 6, and 12 weeks postoperatively, and bone regeneration at the defect site was evaluated by micro-CT, histomorphometry, immunohistochemistry, double-labeling immunofluorescence, and RT-qPCR. The application of exogenous IL-4 reduced activation of NLRP3 inflammasomes by promoting the polarization of M1 macrophages to M2 macrophages, thus promoting bone regeneration at the site of bone defects in aged rats. However, this effect was gradually weakened after the IL-4 intervention was discontinued. Our data confirmed that a strategy to regulate macrophage polarization is also feasible under conditions of immunosenescence, i.e., the local inflammatory microenvironment can be regulated by reducing M1-type macrophages. However, further experiments are needed to determine an exogenous IL-4 intervention that can maintain a more sustained effect.

NALCN is a potential biomarker and therapeutic target in human cancers.

Background: Sodium leak channel non-selective (NALCN), known as a voltage-independent Na+ channel, is increasingly considered to play vital roles in tumorigenesis and metastasis of human cancers. However, no comprehensive pan-cancer analysis of NALCN has been conducted. Our study aims to explore the potential diagnostic, prognostic and therapeutic value of NALCN in human cancers. Methods: Through comprehensive application of datasets from Human Protein Atlas (HPA), The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Enhanced Version of Tumor Immune Estimation Resource (TIMER2.0), Tumor and Immune System Interaction Database (TISIDB), The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), cBioPortal, GeneMANIA and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) databases, we explored the potential roles of NALCN in different cancers. The differential expression, prognostic implications, pathological stages and grades, molecular and immune subtypes, diagnostic accuracy, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, immune checkpoint genes, chemokine genes, major histocompatibility complex (MHC)-related genes, tumor-infiltrating immune cells (TIICs), promoter methylation, mutations, copy number alteration (CNA), and functional enrichment related to NALCN were analyzed. Results: Most cancers lowly expressed NALCN. Upregulated NALCN expression was associated with poor or better prognosis in different cancers. Moreover, NALCN was correlated with clinicopathological features in multiple cancers. NALCN showed high diagnostic accuracy in 5 caner types. NALCN is highly linked with immune-related biomarkers, immune-related genes and TIICs. Significant methylation changes and genetic alteration of NALCN can be observed in many cancers. Enrichment analysis showed that NALCN is closely related to multiple tumor-related signaling pathways. Conclusion: Our study revealed the vital involvement of NALCN in cancer. NALCN can be used as a prognostic biomarker for immune infiltration and clinical outcomes, and has potential diagnostic and therapeutic implications.

351 Single-cell analysis of immune system interactions in the basal cell carcinoma tumor microenvironment

351 Single-cell analysis of immune system interactions in the basal cell carcinoma tumor microenvironment