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Frontiers in Immunology 2024Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse...
Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-β. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.
Topics: Humans; Monocytes; Cell Proliferation; Tumor Microenvironment; Tumor-Associated Macrophages; Neoplasms; Antigens, CD; Female; Macrophages; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Cytokines; T-Lymphocytes; Breast Neoplasms
PubMed: 38903497
DOI: 10.3389/fimmu.2024.1412076 -
Journal of Nanobiotechnology Jun 2024Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen...
Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen species (ROS) in the early and middle stages of SCI severely damage neurons, and most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads to a huge compromise in antioxidant treatment of SCI. Selenium nanoparticles (SeNPs) have excellent ROS scavenging bioactivity, but the toxicity control problem limits the therapeutic window. Here, we propose a synergistic therapeutic strategy of SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) to obtain synergistic ROS scavenging activity. Three different spatial structures of SeNPs@ZIF-8 were synthesized and coated with ferrostatin-1, a ferroptosis inhibitor (FSZ NPs), to achieve enhanced anti-oxidant and anti-ferroptosis activity without toxicity. FSZ NPs promoted the maintenance of mitochondrial homeostasis, thereby regulating the expression of inflammatory factors and promoting the polarization of macrophages into M2 phenotype. In addition, the FSZ NPs presented strong abilities to promote neuronal maturation and axon growth through activating the WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates the powerful and versatile bioactive functions of FSZ NPs for SCI treatment and offers inspiration for other neural injury diseases.
Topics: Spinal Cord Injuries; Animals; Antioxidants; Nanoparticles; Mice; Reactive Oxygen Species; Selenium; Neurons; Ferroptosis; Rats; Macrophages; RAW 264.7 Cells; Nerve Regeneration
PubMed: 38902789
DOI: 10.1186/s12951-024-02610-5 -
Cardiovascular Diabetology Jun 2024This study sought to elucidate the associations of cardiometabolic index (CMI), as a metabolism-related index, with all-cause and cardiovascular mortality among the...
BACKGROUND
This study sought to elucidate the associations of cardiometabolic index (CMI), as a metabolism-related index, with all-cause and cardiovascular mortality among the older population. Utilizing data from the National Health and Nutrition Examination Survey (NHANES), we further explored the potential mediating effect of inflammation within these associations.
METHODS
A cohort of 3029 participants aged over 65 years old, spanning six NHANES cycles from 2005 to 2016, was enrolled and assessed. The primary endpoints of the study included all-cause mortality and cardiovascular mortality utilizing data from National Center for Health Statistics (NCHS). Cox regression model and subgroup analysis were conducted to assess the associations of CMI with all-cause and cardiovascular mortality. The mediating effect of inflammation-related indicators including leukocyte, neutrophil, lymphocyte, systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR) were evaluated to investigate the potential mechanism of the associations between CMI and mortality through mediation package in R 4.2.2.
RESULTS
The mean CMI among the enrolled participants was 0.74±0.66, with an average age of 73.28±5.50 years. After an average follow-up period of 89.20 months, there were 1,015 instances of all-cause deaths and 348 cardiovascular deaths documented. In the multivariable-adjusted model, CMI was positively related to all-cause mortality (Hazard Ratio (HR)=1.11, 95% CI=1.01-1.21). Mediation analysis indicated that leukocytes and neutrophils mediated 6.6% and 13.9% of the association of CMI with all-cause mortality.
CONCLUSION
Elevated CMI is positively associated with all-cause mortality in the older adults. The association appeared to be partially mediated through inflammatory pathways, indicating that CMI may serve as a valuable indicator for poor prognosis among the older population.
Topics: Humans; Male; Aged; Female; Inflammation; Nutrition Surveys; Cardiovascular Diseases; Risk Assessment; Cause of Death; United States; Cardiometabolic Risk Factors; Aged, 80 and over; Time Factors; Prognosis; Inflammation Mediators; Age Factors; Neutrophils; Lymphocyte Count; Biomarkers
PubMed: 38902748
DOI: 10.1186/s12933-024-02251-w -
Respiratory Research Jun 2024There is a desperate for the identification of more accurate and efficient biomarkers for ICI responses in patients with SCLC. (Randomized Controlled Trial)
Randomized Controlled Trial
Tumor mutational burden adjusted by neutrophil-to-lymphocyte ratio serves as a potential biomarker for atezolizumab-treated patients with extensive stage small cell lung cancer.
BACKGROUND
There is a desperate for the identification of more accurate and efficient biomarkers for ICI responses in patients with SCLC.
METHODS
The data of our study was obtained from IMpower133 study. A total of 202 patients with SCLC received the treatment of placebo plus carboplatin plus etoposide (EC) while a total of 201 patients with SCLC received the treatment of atezolizumab plus EC. Overall survival (OS) was compared using Kaplan Meier analyses. Univariate and multivariate Cox regression analysis were used to determine independent prognostic variables affecting OS in patients with SCLC.
RESULTS
We have demonstrated that a higher TMB adjusted by a lower neutrophil-to-lymphocyte ratio (NLR) is significantly correlated with improved OS, in patients with SCLC subject to either atezolizumab or placebo (P = 0.001 for atezolizumab and P = 0.034 for placebo). Moreover, Cox model showed that TMB < 10 mut/Mb adjusted by NLR ≥ median was an independent factor of OS for atezolizumab-treated SCLC patients (hazard ratio [HR], 2.82; 95% confidence interval; 1.52-5.24; P = 0.001). Both univariate and multivariate cox regression analysis showed that for patients with SCLC harboring low NLR and high TMB, survival is significantly longer in those treated with atezolizumab than those treated with placebo. Survival benefit is significantly higher in atezolizumab-treated patients with SCLC than those treated with placebo (P = 0.018 for TMB cutoff = 10 mut/Mb, P = 0.034 for TMB cutoff = 16 mut/Mb).
CONCLUSION
Our findings provide a promising insight into the utility of NLR-adjusted TMB in the prognosis and immune responses in patients with SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Neutrophils; Antibodies, Monoclonal, Humanized; Male; Lung Neoplasms; Female; Lymphocytes; Middle Aged; Aged; Biomarkers, Tumor; Mutation; Neoplasm Staging; Antineoplastic Combined Chemotherapy Protocols; Lymphocyte Count; Double-Blind Method
PubMed: 38902698
DOI: 10.1186/s12931-024-02885-0 -
Journal of Nanobiotechnology Jun 2024Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection...
BACKGROUND
Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse.
RESULTS
The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection.
CONCLUSIONS
These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.
Topics: Animals; Lung Neoplasms; Mice; Deoxycytidine; Hydrogels; Gemcitabine; Humans; Carcinoma, Non-Small-Cell Lung; Necroptosis; Neoplasm Recurrence, Local; Cell Line, Tumor; Immunotherapy; Photothermal Therapy; Wound Infection; Macrophages; Mice, Inbred C57BL; CD8-Positive T-Lymphocytes
PubMed: 38902678
DOI: 10.1186/s12951-024-02568-4 -
Scientific Reports Jun 2024Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures....
Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures. This is particularly important in disease conditions such as asthma and allergic airway disease, where many different cell types are present. In this study, we differentiated CD34+ haematopoietic stem cells towards different populations of MNP in an effort to understand how different cell subtypes present in inflammatory disease microenvironments respond to the common allergen house dust mite (HDM). Using single cell mRNA sequencing, we demonstrate that macrophage subtypes MC and MLC display different patterns of gene expression after HDM challenge, noted especially for the chemokines CXCL5, CXCL8, CCL5 and CCL15. MLC alternatively activated macrophages displayed the greatest changes in expression, while neutrophil and monocyte populations did not respond. Further work investigated how pollutant diesel exhaust particles could modify these transcriptional responses and revealed that CXC but not CC type chemokines were further upregulated. Through the use of diesel particles with adsorbed material removed, we suggest that soluble pollutants on these particles are the active constituents responsible for the modifying effects on HDM. This study highlights that environmental exposures may influence tissue responses dependent on which MNP cell type is present, and that these should be considerations when modelling such events in vitro. Understanding the nuanced responsiveness of different immune cell types to allergen and pollutant exposure also contributes to a better understanding of how these exposures influence the development and exacerbation of human disease.
Topics: Animals; Pyroglyphidae; Humans; Phagocytes; Macrophages; Allergens; Vehicle Emissions; Hematopoietic Stem Cells; Dendritic Cells; Gene Expression Regulation
PubMed: 38902328
DOI: 10.1038/s41598-024-64783-1 -
Scientific Reports Jun 2024Breast cancer, as the most common cancer, has surpassed lung cancer worldwide. The neutrophil-to-lymphocyte ratio (NLR) has been linked to the onset of cancer and its...
Breast cancer, as the most common cancer, has surpassed lung cancer worldwide. The neutrophil-to-lymphocyte ratio (NLR) has been linked to the onset of cancer and its prognosis in recent studies. However, quite a few studies have shown that there is a link between NLR and lymph node metastases in cN0 hormone receptor-positive (HR(+)) breast cancer. The purpose of this study was to evaluate the correlation between NLR and lymph node metastases in cN0 HR(+) breast cancer patients. From January 2012 to January 2022, 220 patients with cN0 HR(+) invasive breast cancers were enrolled in this study. The relationship between NLR and pathological data was statistically examined. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff of NLR, a chi-squared test was used for the univariate analysis, and logistic analysis was used for the multivariate analysis. The NLR had an optimal cutoff of 2.4 when the Jorden index was at a maximum. Patients with axillary lymph node metastases had a higher NLR (P < 0.05). A Univariate analysis showed that there were significant differences in cN0 HR(+) breast cancer with axillary lymph node metastasis among different clinical stages, histological grades, Ki-67 levels, tumor sizes, and NLR levels (P < 0.05). Clinical stage, tumor size, and NLR were found to be independent risk factors for lymph node metastases in multifactorial analysis. In cN0 HR(+) breast cancer, NLR is an independent risk factor for lymph node metastases. An NLR ≥ 2.4 indicates an increased probability of lymph node metastases. An elevated preoperative NLR has a high predictive value for axillary lymph node metastases.
Topics: Humans; Breast Neoplasms; Female; Neutrophils; Lymphatic Metastasis; Middle Aged; Lymphocytes; Adult; Aged; Prognosis; ROC Curve; Receptors, Estrogen; Preoperative Period; Lymph Nodes; Retrospective Studies; Neoplasm Staging
PubMed: 38902284
DOI: 10.1038/s41598-024-63318-y -
International Immunopharmacology Jun 2024Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is caused by an imbalance between pathogens and impaired host immune responses. Mycobacterium avium complex...
OBJECTIVE
Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is caused by an imbalance between pathogens and impaired host immune responses. Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are the two major pathogens that cause NTM-PD. In this study, we sought to dissect the transcriptomes of peripheral blood immune cells at the single-cell resolution in NTM-PD patients and explore potential clinical markers for NTM-PD diagnosis and treatment.
METHODS
Peripheral blood samples were collected from six NTM-PD patients, including three MAB-PD patients, three MAC-PD patients, and two healthy controls. We employed single-cell RNA sequencing (scRNA-seq) to define the transcriptomic landscape at a single-cell resolution. A comprehensive scRNA-seq analysis was performed, and flow cytometry was conducted to validate the results of scRNA-seq.
RESULTS
A total of 27,898 cells were analyzed. Nine T-cells, six mononuclear phagocytes (MPs), and four neutrophil subclusters were defined. During NTM infection, naïve T-cells were reduced, and effector T-cells increased. High cytotoxic activities were shown in T-cells of NTM-PD patients. The proportion of inflammatory and activated MPs subclusters was enriched in NTM-PD patients. Among neutrophil subclusters, an IFIT1 neutrophil subcluster was expanded in NTM-PD compared to healthy controls. This suggests that IFIT1+ neutrophil subcluster might play an important role in host defense against NTM. Functional enrichment analysis of this subcluster suggested that it is related to interferon response. Cell-cell interaction analysis revealed enhanced CXCL8-CXCR1/2 interactions between the IFIT1+ neutrophil subcluster and NK cells, NKT cells, classical mononuclear phagocytes subcluster 1 (classical Mo1), classical mononuclear phagocytes subcluster 2 (classical Mo2) in NTM-PD patients compared to healthy controls.
CONCLUSIONS
Our data revealed disease-specific immune cell subclusters and provided potential new targets of NTM-PD. Specific expansion of IFIT1 neutrophil subclusters and the CXCL8-CXCR1/2 axis may be involved in the pathogenesis of NTM-PD. These insights may have implications for the diagnosis and treatment of NTM-PD.
PubMed: 38901242
DOI: 10.1016/j.intimp.2024.112412 -
PloS One 2024Implant-associated osteomyelitis remains a major orthopaedic problem. As neutrophil swarming to the surgical site is a critical host response to prevent infection,...
Implant-associated osteomyelitis remains a major orthopaedic problem. As neutrophil swarming to the surgical site is a critical host response to prevent infection, visualization and quantification of this dynamic behavior at the native microenvironment of infection will elucidate previously unrecognized mechanisms central to understanding the host response. We recently developed longitudinal intravital imaging of the bone marrow (LIMB) to visualize host cells and fluorescent S. aureus on a contaminated transfemoral implant in live mice, which allows for direct visualization of bacteria colonization of the implant and host cellular responses using two-photon laser scanning microscopy. To the end of rigorous and reproducible quantitative outcomes of neutrophil swarming kinetics in this model, we developed a protocol for robust segmentation, tracking, and quantifications of neutrophil dynamics adapted from Trainable Weka Segmentation and TrackMate, two readily available Fiji/ImageJ plugins. In this work, Catchup mice with tdTomato expressing neutrophils received a transfemoral pin with or without ECFP/EGFP-expressing USA300 methicillin-resistant Staphylococcus aureus (MRSA) to obtain 30-minute LIMB videos at 2-, 4-, and 6-hours post-implantation. The developed semi-automated neutrophil tracking protocol was executed independently by two users to quantify the distance, displacement, speed, velocity, and directionality of the target cells. The results revealed high inter-user reliability for all outcomes (ICC > 0.96; p > 0.05). Consistent with the established paradigm on increased neutrophil swarming during active infection, the results also demonstrated increased neutrophil speed and velocity at all measured time points, and increased displacement at later time points (6 hours) in infected versus uninfected mice (p < 0.05). Neutrophils and bacteria also exhibit directionality during migration in the infected mice. The semi-automated cell tracking protocol provides a streamlined approach to robustly identify and track individual cells across diverse experimental settings and eliminates inter-observer variability.
Topics: Animals; Neutrophils; Mice; Femur; Cell Tracking; Staphylococcal Infections; Disease Models, Animal; Osteomyelitis; Methicillin-Resistant Staphylococcus aureus; Prosthesis-Related Infections; Prostheses and Implants; Staphylococcus aureus; Female
PubMed: 38900759
DOI: 10.1371/journal.pone.0296140 -
Medical Microbiology and Immunology Jun 2024Endogenous antimicrobial peptides (AMPs) play a key role in the host defense against pathogens. AMPs attack pathogens preferentially at the site of entry to prevent...
Endogenous antimicrobial peptides (AMPs) play a key role in the host defense against pathogens. AMPs attack pathogens preferentially at the site of entry to prevent invasive infection. Mycobacterium tuberculosis (Mtb) enters its host via the airways. AMPs released into the airways are therefore likely candidates to contribute to the clearance of Mtb immediately after infection. Since lysozyme is detectable in airway secretions, we evaluated its antimicrobial activity against Mtb. We demonstrate that lysozyme inhibits the growth of extracellular Mtb, including isoniazid-resistant strains. Lysozyme also inhibited the growth of non-tuberculous mycobacteria. Even though lysozyme entered Mtb-infected human macrophages and co-localized with the pathogen we did not observe antimicrobial activity. This observation was unlikely related to the large size of lysozyme (14.74 kDa) because a smaller lysozyme-derived peptide also co-localized with Mtb without affecting the viability. To evaluate whether the activity of lysozyme against extracellular Mtb could be relevant in vivo, we incubated Mtb with fractions of human serum and screened for antimicrobial activity. After several rounds of sub-fractionation, we identified a highly active fraction-component as lysozyme by mass spectrometry. In summary, our results identify lysozyme as an antimycobacterial protein that is detectable as an active compound in human serum. Our results demonstrate that the activity of AMPs against extracellular bacilli does not predict efficacy against intracellular pathogens despite co-localization within the macrophage. Ongoing experiments are designed to unravel peptide modifications that occur in the intracellular space and interfere with the deleterious activity of lysozyme in the extracellular environment.
Topics: Muramidase; Humans; Mycobacterium tuberculosis; Macrophages; Antimicrobial Peptides; Microbial Sensitivity Tests; Microbial Viability
PubMed: 38900248
DOI: 10.1007/s00430-024-00793-0