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Journal For Immunotherapy of Cancer May 2024The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been...
BACKGROUND
The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of PTC immune remodeling and exploration of novel treatment targets.
METHODS
This study conducted a single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured from 14 patients diagnosed with adjacent tissues, non-progressive PTC or progressive PTC. Key findings were authenticated through spatial transcriptomics RNA sequencing, immunohistochemistry, multiplex immunohistochemistry, and an independent bulk RNA-seq data set containing 502 samples.
RESULTS
A total of 151,238 individual cells derived from 18 adjacent tissues, non-progressive PTC and progressive PTC specimens underwent scRNA-seq analysis. We found that progressive PTC exhibits the following characteristics: a significant decrease in overall immune cells, enhanced immune evasion of tumor cells, and disrupted antigen presentation function. Moreover, we identified a subpopulation of lysosomal associated membrane protein 3 (LAMP3) dendritic cells (DCs) exhibiting heightened infiltration in progressive PTC and associated with advanced T stage and poor prognosis of PTC. LAMP3 DCs promote CD8 T cells exhaustion (mediated by NECTIN2-TIGIT) and increase infiltration abundance of regulatory T cells (mediated by chemokine (C-C motif) ligand 17 (CCL17)-chemokine (C-C motif) receptor 4 (CCR4)) establishing an immune-suppressive microenvironment. Ultimately, we unveiled that progressive PTC tumor cells facilitate the retention of LAMP3 DCs within the tumor microenvironment through NECTIN3-NECTIN2 interactions, thereby rendering tumor cells more susceptible to immune evasion.
CONCLUSION
Our findings expound valuable insights into the role of the interaction between LAMP3 DCs and T-cell subpopulations and offer new and effective ideas and strategies for immunotherapy in patients with progressive PTC.
Topics: Humans; Dendritic Cells; Thyroid Cancer, Papillary; Lysosomal-Associated Membrane Protein 3; Thyroid Neoplasms; Male; Female; Tumor Microenvironment; Middle Aged; Tumor Escape; T-Lymphocyte Subsets; Neoplasm Proteins
PubMed: 38816233
DOI: 10.1136/jitc-2024-008983 -
Turkish Journal of Medical Sciences 2023The common disease gastric adenocarcinoma (GAC) has a high morbidity and mortality, so there is an urgent need for research to explore new diagnostic markers and...
BACKGROUND/AIM
The common disease gastric adenocarcinoma (GAC) has a high morbidity and mortality, so there is an urgent need for research to explore new diagnostic markers and therapeutic targets. This investigation was carried out to investigate the expression of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3B) in GAC and its effects on tumor progression.
MATERIALS AND METHODS
Samples were collected from patients who underwent radical gastrectomy from January 2021 to December 2022. Along with the normal gastric epithelial cell lines GES-1 and SGC-7901, the AGS, MGC-803, and MSN-45 human gastric cancer cell lines were used to confirm SMPDL3B expression. RT-qPCR, Western blot, immunohistochemical, cell proliferation, assay of wound healing, transwell migration assay, invasion assay, flow cytometry, and immune evaluation experiments were carried out.
RESULTS
SMPDL3B was found to be substantially expressed in GAC, and this condition has a bad prognosis. By establishing SMPDL3B knockdown and overexpression of GAC cell lines, this study confirmed that SMPDL3B promoted tumor cell proliferation, migration, and invasion. Additional bioinformatics research revealed a connection between SMPDL3B and immune cell infiltration in the GAC immunological microenvironment, which enhanced tumor cell proliferation by promoting the infiltration content of M2 macrophages.
CONCLUSION
This study determined the function of SMPDL3B for the clinical diagnosis, prediction, and novel management of GAC.
Topics: Humans; Stomach Neoplasms; Adenocarcinoma; Cell Proliferation; Cell Line, Tumor; Macrophages; Cell Movement; Sphingomyelin Phosphodiesterase; Disease Progression; Male; Female; Middle Aged; Tumor Microenvironment
PubMed: 38813495
DOI: 10.55730/1300-0144.5732 -
International Journal of Nanomedicine 2024Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in...
INTRODUCTION
Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy.
METHODS
Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections.
RESULTS
The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments.
CONCLUSION
MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.
Topics: Animals; Cisplatin; Lung Neoplasms; Mice; Imiquimod; Mice, Inbred C57BL; Hydrogels; Apoptosis; Nanostructures; Photothermal Therapy; Antineoplastic Agents; Cell Line, Tumor; Drug Delivery Systems; Humans; Temperature; Dendritic Cells; Drug Carriers; Carcinoma, Lewis Lung
PubMed: 38813391
DOI: 10.2147/IJN.S449541 -
Frontiers in Immunology 2024Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches...
INTRODUCTION
Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches hematopoietic precursors in the bone marrow to sustain a memory-like phenotype. Dendritic cells (DCs) can exhibit memory-like responses, enhanced upon subsequent exposure to a pathogen; however, whether this imprinting is lineage and stimulus-restricted is still being determined. Nevertheless, the functional consequences of DCs training on the adaptive and protective immune response against non-infectious diseases remain unresolved.
METHODS
We evaluated the effect of the nontoxic cholera B subunit (CTB), LPS and LTA in the induction of trained immunity in murine DCs revealed by TNFa and LDH expression, through confocal microscopy. Additionally, we obtained bone marrow DCs (BMDCs) from mice treated with CTB, LPS, and LTA and evaluated training features in DCs and their antigen-presenting cell capability using multiparametric cytometry. Finally, we design an experimental melanoma mouse model to demonstrate protection induced by CTB-trained DCs in vivo.
RESULTS
CTB-trained DCs exhibit increased expression of TNFa, and metabolic reprogramming indicated by LDH expression. Moreover, CTB training has an imprint on DC precursors, increasing the number and antigen-presenting function in BMDCs. We found that training by CTB stimulates the recruitment of DC precursors and DCs infiltration at the skin and lymph nodes. Interestingly, training-induced by CTB promotes a highly co-stimulatory phenotype in tumor-infiltrating DCs (CD86+) and a heightened functionality of exhausted CD8 T cells (Ki67+, GZMB+), which were associated with a protective response against melanoma challenge in vivo.
CONCLUSION
Our work indicates that CTB can induce innate immune training on DCs, which turns into an efficient adaptive immune response in the melanoma model and might be a potential immunotherapeutic approach for tumor growth control.
Topics: Animals; Dendritic Cells; Mice; CD8-Positive T-Lymphocytes; Cholera Toxin; Melanoma, Experimental; Mice, Inbred C57BL; Immunity, Innate; Female; Immunologic Memory; Trained Immunity
PubMed: 38812523
DOI: 10.3389/fimmu.2024.1362289 -
Frontiers in Immunology 2024Chondroitin sulfate synthase 3 (CHSY3) is an important enzyme that regulates glycosylation, but its role in tumors has not been determined. Here, we showed that high...
Chondroitin sulfate synthase 3 (CHSY3) is an important enzyme that regulates glycosylation, but its role in tumors has not been determined. Here, we showed that high CHSY3 expression promotes proliferation in gastric cancer (GC) cells and is associated with poor prognosis in GC patients. We analyzed the immunohistochemistry data of 150 gastric cancer patients to determine the clinicopathological and survival significance of CHSY3. Immunofluorescence was used to detect the colocalization of CHSY3 with infiltrating immune cells. Additionally, CHSY3 was predominantly found in tumor tissues and showed higher abundance compared to matched adjacent tissues. High CHSY3 expression was associated with more advanced tumor stage, higher recurrence risk and worse survival. Immunohistochemistry and bioinformatic analysis revealed that CHSY3 expression was significantly positively correlated with tumor-associated macrophage (TAM) infiltration. Moreover, after knocking down CHSY3, the proliferation of cells was decreased, and the migration ability was reduced, as shown by scratch, monoclonal and transwell assays. In conclusion, this study revealed that CHSY3 has a tumor-promoting effect on GC, suggesting a novel therapeutic strategy against this disease.
Topics: Humans; Stomach Neoplasms; Prognosis; Female; Male; Cell Proliferation; Middle Aged; Cell Line, Tumor; Cell Movement; Biomarkers, Tumor; Tumor-Associated Macrophages; Aged; Gene Expression Regulation, Neoplastic
PubMed: 38812506
DOI: 10.3389/fimmu.2024.1364979 -
Frontiers in Immunology 2024The effects of cold exposure on whole-body metabolism in humans have gained increasing attention. Brown or beige adipose tissues are crucial in cold-induced...
OBJECTIVES
The effects of cold exposure on whole-body metabolism in humans have gained increasing attention. Brown or beige adipose tissues are crucial in cold-induced thermogenesis to dissipate energy and thus have the potential to combat metabolic disorders. Despite the immune regulation of thermogenic adipose tissues, the overall changes in vital immune cells during distinct cold periods remain elusive. This study aimed to discuss the overall changes in immune cells under different cold exposure periods and to screen several potential immune cell subpopulations on thermogenic regulation.
METHODS
Cibersort and mMCP-counter algorithms were employed to analyze immune infiltration in two (brown and beige) thermogenic adipose tissues under distinct cold periods. Changes in some crucial immune cell populations were validated by reanalyzing the single-cell sequencing dataset (GSE207706). Flow cytometry, immunofluorescence, and quantitative real-time PCR assays were performed to detect the proportion or expression changes in mouse immune cells of thermogenic adipose tissues under cold challenge.
RESULTS
The proportion of monocytes, naïve, and memory T cells increased, while the proportion of NK cells decreased under cold exposure in brown adipose tissues.
CONCLUSION
Our study revealed dynamic changes in immune cell profiles in thermogenic adipose tissues and identified several novel immune cell subpopulations, which may contribute to thermogenic activation of adipose tissues under cold exposure.
Topics: Thermogenesis; Animals; Mice; Adipose Tissue, Brown; Cold Temperature; Mice, Inbred C57BL; Male; Adipose Tissue, Beige; Adipose Tissue; Killer Cells, Natural; Monocytes
PubMed: 38812501
DOI: 10.3389/fimmu.2024.1375138 -
Frontiers in Bioscience (Landmark... May 2024The epithelia of the intestine perform various functions, playing a crucial role in providing a physical barrier and an innate immune defense against infections. By...
BACKGROUND
The epithelia of the intestine perform various functions, playing a crucial role in providing a physical barrier and an innate immune defense against infections. By generating a "three-dimensional" (3D) model of cell co-cultures using the IPEC-J2 cell line and porcine blood monocyte-derived macrophages (MDMs), we are getting closer to mimicking the porcine intestine Methods: The effect of B1/1 and CCM 7158 (indicator strain) on the relative gene expression of interleukins (IL-1β, IL-6, IL-8, IL-18 and IL-10), genes encoding receptors for TLR4 and TLR2, tight junction proteins such as claudin-1 (CLDN1), occludin (OCLN) and important antimicrobial proteins such as lumican (LUM) and olfactomedin-4 (OLMF-4) was monitored in this model.
RESULTS
The results obtained from this pilot study point to the immunomodulatory potential of newly isolated B1/1, as it was able to suppress the enhanced pro-inflammatory response to lipopolysaccharide (LPS) challenge in both cell types. B1/1 was even able to up-regulate the mRNA levels of genes encoding antimicrobial proteins LUM and OLFM-4 and to increase tight junction (TJ)-related genes and , which were significantly down-regulated in LPS-induced IPEC-J2 cells. Conversely, CCM 7158, chosen as an indicator lactic acid bacteria (LAB) strain, increased the mRNA levels of the investigated pro-inflammatory cytokines (IL-18, IL-6, and IL-1β) in MDMs when LPS was simultaneously applied to basally deposited macrophages. Although CCM 7158 induced the production of pro-inflammatory cytokines, synchronous up-regulation of the anti-inflammatory cytokine IL-10 was detected in both LAB strains used in both cell cultures.
CONCLUSIONS
The obtained results suggest that the recently isolated LAB strain B1/1 has the potential to alleviate epithelial disruption caused by LPS and to influence the production of antimicrobial molecules by enterocytes.
Topics: Animals; Cytokines; Swine; Limosilactobacillus reuteri; Cell Line; Macrophages; Antimicrobial Peptides; Coculture Techniques
PubMed: 38812316
DOI: 10.31083/j.fbl2905180 -
Frontiers in Bioscience (Landmark... May 2024Gastric adenocarcinoma (GAC) is a malignant tumor with the highest incidence in the digestive system. Macrophages have been proven to play important roles in tumor...
BACKGROUND
Gastric adenocarcinoma (GAC) is a malignant tumor with the highest incidence in the digestive system. Macrophages have been proven to play important roles in tumor microenvironment.
METHODS
Herein, single-cell RNA sequencing (scRNA-seq) profiles from the Gene Expression Omnibus (GEO) and bulk RNA-seq data from the Cancer Genome Atlas (TCGA) database were utilized to construct a macrophage marker gene signature (MMGS) to predict the prognosis of GAC patients. Subsequently, a risk score model based on the MMGS was built to predict the prognosis of GAC patients; further, this was validated in the GEO cohort. The risk score categorized patients into the high- and low-risk groups. A nomogram model based on the risk score and clinic-pathological characteristics was developed.
RESULTS
Seven genes, , , , , , , and , were included in the risk score model. Patients with a low-risk score showed a better prognosis. The MMGS had good sensitivity and specificity for predicting the prognosis inGAC patients. The risk score was an independent prognostic factor. The constructed nomogram exhibited favorable predictability and reliability for predicting GAC prognosis.
CONCLUSION
In conclusion, the risk score model based on the seven MMGSs performed well in the predicting prognosis of GAC patients. Our study may provide new insights into clinical decision-making for the personalized treatment of patients with gastric cancer (GC).
Topics: Humans; Stomach Neoplasms; Prognosis; Adenocarcinoma; Computational Biology; Biomarkers, Tumor; Nomograms; Male; Female; Gene Expression Regulation, Neoplastic; Macrophages; Tumor Microenvironment; Middle Aged; Transcriptome; Gene Expression Profiling; Aged
PubMed: 38812299
DOI: 10.31083/j.fbl2905172 -
Scientific Reports May 2024HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by...
HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human βm (hβm) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3-/-), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.
Topics: Animals; HLA-B27 Antigen; Transcription Factor CHOP; Colitis; Rats; Endoplasmic Reticulum Stress; Spondylarthritis; Disease Models, Animal; Interleukin-23; Humans; Interleukin-23 Subunit p19; Rats, Transgenic; Interleukin-17; Colon; Macrophages
PubMed: 38811719
DOI: 10.1038/s41598-024-62940-0 -
Scientific Reports May 2024Atherosclerosis is the build-up of fatty plaques within blood vessel walls, which can occlude the vessels and cause strokes or heart attacks. It gives rise to both...
Atherosclerosis is the build-up of fatty plaques within blood vessel walls, which can occlude the vessels and cause strokes or heart attacks. It gives rise to both structural and biomolecular changes in the vessel walls. Current single-modality imaging techniques each measure one of these two aspects but fail to provide insight into the combined changes. To address this, our team has developed a dual-modality imaging system which combines optical coherence tomography (OCT) and fluorescence imaging that is optimized for a porphyrin lipid nanoparticle that emits fluorescence and targets atherosclerotic plaques. Atherosclerosis-prone apolipoprotein (Apo)e mice were fed a high cholesterol diet to promote plaque development in descending thoracic aortas. Following infusion of porphyrin lipid nanoparticles in atherosclerotic mice, the fiber-optic probe was inserted into the aorta for imaging, and we were able to robustly detect a porphyrin lipid-specific fluorescence signal that was not present in saline-infused control mice. We observed that the nanoparticle fluorescence colocalized in areas of CD68 macrophages. These results demonstrate that our system can detect the fluorescence from nanoparticles, providing complementary biological information to the structural information obtained from simultaneously acquired OCT.
Topics: Tomography, Optical Coherence; Animals; Plaque, Atherosclerotic; Nanoparticles; Mice; Porphyrins; Optical Imaging; Disease Models, Animal; Atherosclerosis; Macrophages; Lipoproteins, HDL
PubMed: 38811670
DOI: 10.1038/s41598-024-63132-6