High Macrophage Infiltration Research Articles

Heterogeneous immune landscapes and macrophage dynamics in primary and lung metastatic adenoid cystic carcinoma of the head and neck.

Recurrent or metastatic adenoid cystic carcinoma (ACC) of the head and neck is rare and highly aggressive. Due to the ineffectiveness of immune checkpoint therapies, this study aims to investigate the tumor immune microenvironment of primary tumor tissues and lung metastatic tissues and to comprehend the challenges of immunotherapy. We analyzed RNA sequencing data and constructed immune landscapes from 25 primary tumors and 34 lung metastases. The data were then validated by immunohistochemistry and single-cell sequencing analysis. Compared to adjacent normal tissues, both primary and lung metastatic ACC showed low immune infiltration. Lung metastases had higher immune infiltration levels and antigen presentation scores but also higher T cell exclusion and dysfunction scores. Single-cell sequencing data and immunohistochemistry revealed abundant immunosuppressive tumor-associated macrophages in lung metastases. Patients with high M2 macrophage infiltration had shorter lung metastasis-free survival. Primary and lung metastatic ACC exhibit heterogeneous tumor immune microenvironments. Higher immune cell infiltration in lung metastases is countered by the presence of suppressive tumor-associated macrophages, which may limit effective anti-tumor responses.

Temporal genomic analysis of homogeneous tumor models reveals key regulators of immune evasion in melanoma

Abstract Low intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogeneous tumors are variably aggressive, and the immunological factors impacting aggressiveness remain understudied. Here, we analyzed the mechanisms underlying immune escape in murine tumors with low ITH. We used immunophenotyping and single-cell RNA sequencing to compare the temporal growth of in-vivo transplanted, genetically similar rejected vs. non-rejected single-cell clones. Non-rejected clones showed high infiltration of tumor-associated macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate regulators, identified Mif (macrophage migration inhibitory factor) as a major contributor to immune rejection. Mif knockout resulted in smaller tumors and reduced TAM infiltration. These results were validated in melanoma patient data. Overall, our homogeneous tumor system can uncover factors regulating growth variability and identifies Mif as critical in aggressive melanoma.

An Innovative Telomere-associated Prognosis Model in AML: Predicting Immune Infiltration and Treatment Responsiveness.

To build an innovative telomere-associated scoring model to predict prognosis and treatment responsiveness in acute myeloid leukemia (AML). AML is a highly heterogeneous malignant hematologic disorder with a poor prognosis. While telomere maintenance is frequently observed in tumors, investigations into telomere-related genes (TRGs) in AML remain limited. This study aimed to identify prognostic TRGs using the least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression, evaluate their predictive value, explore the association between TRG scores and immune cell infiltration, and assess the sensitivity of high-scoring AML patients to chemotherapeutic agents. Univariate Cox regression analysis was conducted on the TCGA cohort to identify prognostic TRGs and to develop the TRG scoring model using LASSO-Cox and multivariate Cox regression. Validation was performed on the GSE37642 cohort. Immune cell infiltration patterns were assessed through computational analysis, and the sensitivity to chemotherapeutic agents was evaluated. Thirteen prognostic TRGs were identified, and a seven-TRG scoring model (including NOP10, OBFC1, PINX1, RPA2, SMG5, MAPKAPK5, and SMN1) was developed. Higher TRG scores were associated with a poorer prognosis, as confirmed in the GSE37642 cohort, and remained an independent prognostic factor even after adjusting for other clinical characteristics. The high-score group was characterized by elevated infiltration of B cells, T helper cells, natural killer cells, tumor-infiltrating lymphocytes, regulatory T (Treg) cells, M2 macrophages, neutrophils, and monocytes, along with reduced infiltration of gamma delta T cells, CD4- T cells, and resting mast cells. Moreover, high infiltration of M2 macrophages and Tregs was associated with poor overall survival compared to low infiltration. Notably, high-risk AML patients were resistant to Erlotinib, Parthenolide, and Nutlin-3a, but sensitive to AC220, Midostaurin, and Tipifarnib. Additionally, using RT-qPCR, we observed significantly higher expression of two model genes, OBFC1 and SMN1, in AML tissues compared to control tissues. This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.

Chromium and Palmitic Acid Supplementation Modulate Adipose Tissue Insulin Sensitivity in Postpartum Dairy Cows

Periparturient dairy cows exhibit intense lipolysis driven by reduced dry matter intake, enhanced energy needs, and the loss of adipose tissue (AT) insulin sensitivity. Extended periods of low insulin sensitivity and negative energy balance induce lipolysis dysregulation, leading to increased disease susceptibility and poor lactation performance. Chromium (Cr) supplementation improves systemic insulin sensitivity, while palmitic acid (PA) increases energy availability for milk production. However, the effect of supplementing Cr and PA alone or in combination on insulin sensitivity in AT is unknown. Thirty-two multiparous cows were used in a randomized complete block design experiment and randomly assigned to one of 4 diets fed from 1 to 24 DIM. Diets included: control, no supplementation (CON, n = 8); Cr (Cr-propionate at 0.45 ppm Cr/kg DM, n = 8); PA (1.5% DM, n = 8); or Cr+PA (n = 8). Plasma samples were collected at -13 ± 5.1 d prepartum (PreP), and 14.4 ± 1.9d (PP1) and 21 ± 1.9d (PP2) after calving for albumin, BHB, BUN, calcium, cholesterol, glucose, nonesterified fatty acids (NEFA), total protein, iron, transferrin, triglycerides, and oxylipids quantification. Subcutaneous AT (SCAT) explants were collected at PreP, PP1 and PP2 and incubated in the presence of the lipolytic agent isoproterenol (ISO = 1 µM, BASAL = 0 µM) for 3 h. The antilipolytic effect of insulin (1µL/L) on SCAT explants was evaluated during ISO stimulation (IN+ISO). Lipolysis was quantified by glycerol release in the media (nmol glycerol/mg AT). Macrophage infiltration and adipocyte size were measured using hematoxylin and eosin-stained AT sections and immunohistochemistry. Cr tended to reduce postpartum NEFA concentrations when compared with CON, PA, and Cr+PA. Likewise, Cr increased the percentage of large adipocytes (>9000 µm2) postpartum compared with other diets. In line with higher lipid content, Cr-fed cows had higher ex-vivo BASAL lipolysis at PP2 when compared with PA and Cr+PA. ISO induced higher lipolysis at PP1 and PP2 but it was not affected by Cr and PA. IN+ISO reduced lipolysis by 29.91 ± 11% in Cr compared with ISO. In contrast, IN+ISO did not affect ISO lipolysis in CON, PA, and Cr+PA. Plasma transferrin was reduced by Cr. At PP2, PA cows had 3.3-fold higher macrophage infiltration in SCAT when compared with CON and Cr. Plasma 9-HODE and 9-oxoODE were increased by Cr+PA. PA increased plasma 13-oxoODE and Cr increased the ratio of 13-HODE:13-oxoODE. PA increased 5-iso Prostaglandin F2α-VI. Our results demonstrate that supplementing Cr during the immediate postpartum enhances SCAT insulin sensitivity and lipid accumulation. Further studies should determine the effects and mechanisms of action of Cr and PA on AT lipogenesis, adipogenesis, and their impact on lactation performance.

A risk scoring model based on M2 macrophage-related genes for predicting prognosis of HBV-related hepatocellular carcinoma

To investigate the prognostic value of M2 macrophage-related genes (MRG) in hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC). The transcriptome data of 73 patients with HBV-related HCC were obtained from TCGA database, and the MRG modules were identified by WGCNA. The MRG-based risk scoring model was constructed by LASSO regression analysis and validated using an external dataset. The correlation of the risk score with immune cell infiltration and drug sensitivity of HCC were analyzed with CIBERSORT and R. pRRophetic. The signaling pathways of the differential genes between the high- and low-risk groups were investigated using GSVA and GSEA enrichment analyses, and MRG expressions at the single cell level were validated using R.Seurat. The cell interaction intensity was analyzed by R.Cellchat to identify important cell types related to HCC progression. MRG expression levels were detected by RT-qPCR in THP-1 cells with HCC-conditioned medium-induced M2 polarization and in HBV-positive HCC cells. A high M2 macrophage infiltration level was significantly correlated with a poor prognosis of HCC, and 5 hub MRG (VTN, GCLC, PARVB, TRIM27, and GMPR) were identified. The overall survival of HCC patients was significantly lower in the high-risk than in the low-risk group. The high- and the low-risk groups showed significant enrichment of M2 macrophages and na?ve B cells, respectively, and were sensitive to BI. 2536 and to AG. 014699, AKT. inhibitor. Ⅷ, AZD. 0530, AZD7762, and BMS. 708163, respectively. The proliferation-related and metabolism-related pathways were enriched in the high-risk group, where monocytes showed the most active cell interactions during HCC progression. VTN was significantly upregulated in HCC cell lines, while GCLC, PARVB, TRIM27, and GMPR were upregulated in M2 THP-1 cells. The MRG-based risk scoring model can accurately predict the prognosis of HBV-related HCC and reveal the differences in tumor microenvironment to guide precision treatment of the patients.

Tea polyphenol-engineered hybrid cellular nanovesicles for cancer immunotherapy and androgen deprivation therapy.

Androgen deprivation therapy (ADT) is a crucial and effective strategy for prostate cancer, while systemic administration may cause profound side effects on normal tissues. More importantly, the ADT can easily lead to resistance by involving the activation of NF-κB signaling pathway and high infiltration of M2 macrophages in tumor microenvironment (TME). Herein, we developed a biomimetic nanotherapeutic platform by deriving cell membrane nanovesicles from cancer cells and probiotics to yield the hybrid cellular nanovesicles (hNVs), loading flutamide (Flu) into the resulting hNVs, and finally modifying the hNVs@Flu with Epigallocatechin-3-gallate (EGCG). In this nanotherapeutic platform, the hNVs significantly improved the accumulation of hNVs@Flu-EGCG in tumor sites and reprogramed immunosuppressive M2 macrophages into antitumorigenic M1 macrophages, the Flu acted on androgen receptors and inhibited tumor proliferation, and the EGCG promoted apoptosis of prostate cancer cells by inhibiting the NF-κB pathway, thus synergistically stimulating the antitumor immunity and reducing the side effects and resistance of ADT. In a prostate cancer mouse model, the hNVs@Flu-EGCG significantly extended the lifespan of mice with tumors and led to an 81.78% reduction in tumor growth compared with the untreated group. Overall, the hNVs@Flu-EGCG are safe, modifiable, and effective, thus offering a promising platform for effective therapeutics of prostate cancer.

Unlocking the potential: A novel prognostic index signature for acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by challenges in treatment, including drug resistance and frequent relapse. Recent research highlights the crucial roles of tumor microenvironment (TME) in assisting tumor cell immune escape and promoting tumor aggressiveness. This study delves into the interplay between AML and TME. Through the exploration of potential driver genes, we constructed an AML prognostic index (AMLPI). Cross-platform data and multi-dimensional internal and external validations confirmed that the AMLPI outperforms existing models in terms of areas under the receiver operating characteristic curves, concordance index values, and net benefits. High AMLPIs in AML patients were indicative of unfavorable prognostic outcomes. Immune analyses revealed that the high-AMLPI samples exhibit higher expression of HLA-family genes and immune checkpoint genes (including PD1 and CTLA4), along with lower T cell infiltration and higher macrophage infiltration. Genetic variation analyses revealed that the high-AMLPI samples associate with adverse variation events, including TP53 mutations, secondary NPM1 co-mutations, and copy number deletions. Biological interpretation indicated that ALDH2 and SPATS2L contribute significantly to AML patient survival, and their abnormal expression correlates with DNA methylation at cg12142865 and cg11912272. Drug response analyses revealed that different AMLPI samples tend to have different clinical selections, with low-AMLPI samples being more likely to benefit from immunotherapy. Finally, to facilitate broader access to our findings, a user-friendly and publicly accessible webserver was established and available at http://bioinfor.imu.edu.cn/amlpi. This server provides tools including TME-related AML driver genes mining, AMLPI construction, multi-dimensional validations, AML patients risk assessment, and figures drawing.

Predictive value of peripheral blood leukocytes-based methylation of Long non-coding RNA MALAT1 and H19 in the chemotherapy effect and prognosis of gastric cancer

BackgroundThe predictive value of the methylation of Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and H19 promoters in peripheral blood leukocytes as a non-invasive biomarker for the chemotherapy effect and prognosis gastric cancer (GC) is unclear. MethodsThe DNA methylation of H19 and MALAT1 between chemotherapy-sensitive and non-sensitive groups and between groups with better and worse survival of GC was compared using regression analyses. Several predictive nomograms were constructed. The genetic alteration of MALAT1 and H19 and the association between gene expression and immune status in GC were also investigated using bioinformatics analysis. ResultsHigher genetic methylations in peripheral blood were noticed in GC groups with poorer survival. The constructed nomograms presented strong predictive values for the chemotherapy effect and 3-year survival of disease-free survival, progression-free survival, and overall survival, with the area under the curve as 0.838, 0.838, 0.912, and 0.925, respectively. Significant correlations between MALAT1 or H19 expression and marker genes of immune checkpoints and immune pathways were noticed. The high infiltration of macrophages in H19-high and low infiltration of CD8+ T cells in MALAT1-high groups were associated with worse survival of GC. ConclusionsMALAT1 and H19 have the potential to predict the chemotherapy response and clinical outcomes of GC.

MiRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8%± 2.6%/27.9%± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma invivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

Polarization of M2 Tumor-Associated Macrophages (TAMs) in Cancer Immunotherapy.

We have witnessed in the last decade new milestones in the treatment of various resistant cancers with new immunotherapeutic modalities. These advances have resulted in significant objective durable clinical responses in a subset of cancer patients. These findings strongly suggested that immunotherapy should be considered for the treatment of all subsets of cancer patients. Accordingly, the mechanisms underlying resistance to immunotherapy must be explored and develop new means to target these resistant factors. One of the pivotal resistance mechanisms in the tumor microenvironment (TME) is the high infiltration of tumor-associated macrophages (TAMs) that are highly immunosuppressive and responsible, in large part, of cancer immune evasion. Thus, various approaches have been investigated to target the TAMs to restore the anti-tumor immune response. One approach is to polarize the M2 TAMS to the M1 phenotype that participates in the activation of the anti-tumor response. In this review, we discuss the various and differential properties of the M1 and M2 phenotypes, the molecular signaling pathways that participate in the polarization, and various approaches used to target the polarization of the M2 TAMs into the M1 anti-tumor phenotype. These approaches include inhibitors of histone deacetylases, PI3K inhibitors, STAT3 inhibitors, TLR agonists, and metabolic reprogramming. Clearly, due to the distinct features of various cancers and their heterogeneities, a single approach outlined above might only be effective against some cancers and not others. In addition, targeting by itself may not be efficacious unless used in combination with other therapeutic modalities.

RSK4 promotes the macrophage recruitment and M2 polarization in esophageal squamous cell carcinoma

High infiltration of tumor-associated macrophages (TAMs) participates in host immunity and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Ribosomal s6 kinase 4 (RSK4) has been shown to be aberrantly overexpressed in ESCC. The role of RSK4 in cytokine secretion and its impact on macrophage recruitment and M2 polarization remains unclear. Therefore, a thorough understanding of RSK4 is needed to expand our knowledge of its therapeutic potential. Herein, RSK4 expression in human ESCC tissues and a xenograft mouse model was positively correlated with high infiltration of M0 and M2 macrophages which is positively associated with unfavorable overall survival outcomes and treatment resistance in patients with ESCC. In vitro experiments revealed that RSK4 derived from ESCC cells promoted macrophage recruitment and M2 polarization by enhancingsoluble intercellular adhesion molecule-1 (sICAM-1) secretion via direct and indirect STAT3 phosphorylation. Furthermore, RSK4-induced macrophages enhanced tumor proliferation, migration, and invasion by secreting C-C motif chemokine ligand 22 (CCL22). We further showed that patients with elevated CD68 and CD206 expression had unfavorable overall survival. Collectively, these results demonstrate that RSK4 promotes the macrophage recruitment and M2 polarization by regulating the STAT3/ICAM-1 axis in ESCC, influencing tumor progression primarily in a CCL22-dependent manner. These data also offer valuable insights for developing novel agents for the treatment of ESCC.

Bioinformatics analysis identifies potential m6A hub genes in the pathogenesis of intracerebral hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is a type of stroke associated with a high rate of disability and mortality. The role of N6-methyladenosine (m6A) in ICH remains unclear. MethodsScreening of m6A DEGs by differentially expressed genes (DEGs) analysis. m6A hub genes in ICH were identified by protein-protein interaction (PPI) networks. Pearson correlation tests were used to explore the relationship between m6A hub genes and DNA methylation. m6A hub genes were examined by ROC curves for their ability to predict ICH occurrence. Immune cell infiltration and m6A hub gene correlation in ICH were analysed using the CIBERSORT algorithm. Construction of ceRNA networks and enrichment analysis by GO/KEGG. ResultsA total of 12 m6A regulatory enzymes were differentially expressed after ICH. the PPI network screened three m6A hub genes, including YTHDF2, FTO and HNRNPA2B1. A high expression of YTHDF2 was associated with DNA hypomethylation after ICH and could better predict the development of ICH. yTHDF2 was associated with high infiltration of M1 macrophages after ICH. A ceRNA network was constructed based on the m6A central gene with target genes enriched in transcriptional regulation and the LKB1 signalling pathway. ConclusionM6A modifications are involved in the progression of ICH. YTHDF2, an m6A key gene, may regulate ICH progression by promoting infiltration of M1 macrophages or through the ceRNA network.

Exploration and validation of a novel signature of seven necroptosis-related genes to improve the clinical outcome of hepatocellular carcinoma

Necroptosis has been reported to be involved in cancer progression and associated with cancer prognosis. However, the prognostic values of necroptosis-related genes (NRGs) in hepatocellular carcinoma (HCC) remain largely unknown. This study aimed to build a signature on the basis of NRGs to evaluate the prognosis of HCC patients. In this study, using bioinformatic analyses of transcriptome sequencing data of HCC (n = 370) from The Cancer Genome Atlas (TCGA) database, 63 differentially expressed NRGs between HCC and adjacent normal tissues were determined. 24 differentially expressed NRGs were found to be related with overall survival (OS). Seven optimum NRGs, determined using Lasso regression and multivariate Cox regression analysis, were used to construct a new prognostic risk signature for predicting the prognosis of HCC patients. Then survival status scatter plots and survival curves demonstrated that the prognosis of patients with high-Riskscore was worse. The prognostic value of this 7-NRG signature was validated by the International Cancer Genome Consortium (ICGC) cohort and a local cohort (Wenzhou, China). Notably, Riskscore was defined as an independent risk factor for HCC prognosis using multivariate cox regression analysis. Immune infiltration analysis suggested that higher macrophage infiltration was found in patients in the high-risk group. Finally, enhanced 7 NRGs were found in HCC tissues by immunohistochemistry. In conclusion, a novel 7-NRG prognostic risk signature is generated, which contributes to the prediction in the prognosis of HCC patients for the clinicians.

SILAC proteomics based on 3D cell spheroids unveils the role of RAC2 in regulating the crosstalk between triple-negative breast cancer cells and tumor-associated macrophages

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is characterized by a high infiltration of tumor-associated macrophages (TAMs). TAMs contribute significantly to tumor progression by intricately interacting with tumor cells. Deeply investigating the interaction between TNBC cells and TAMs is of great importance for finding potential biomarkers and developing novel therapeutic strategies to further improve the clinical outcomes of TNBC patients. In this study, we confirmed the interplay using both 3D and 2D co-culture models. The stable-isotype labeling by amino acids in cell culture (SILAC)-based quantitative proteomics was conducted on 3D cell spheroids containing TNBC cells and macrophages to identify the potential candidate in regulating the crosstalk between TNBC and TAMs. Ras-related C3 botulinum toxin substrate 2 (RAC2) was identified as a potential molecule for further exploration, given its high expression in TNBC and positive correlation with M2 macrophage infiltration. The suppression of RAC2 inhibited TNBC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro. Meanwhile, knocking down RAC2 in TNBC cells impaired macrophage recruitment and M2 polarization. Mechanistically, RAC2 exerted its roles in TNBC cells and TAMs by regulating the activation of P65 NF-κB and P38 MAPK, while TAMs further elevated RAC2 expression and P65 NF-κB activation by secreting soluble mediators including IL-10. These findings highlight the significance of RAC2 as a crucial molecule in the crosstalk between TNBC and TAMs, suggesting it could be a promising therapeutic target in TNBC.

Establishment of head and neck squamous cell carcinoma mouse models for cetuximab resistance and sensitivity.

Aim: Acquired resistance to the targeted agent cetuximab poses a significant challenge in finding effective anti-cancer treatments for head and neck squamous cell carcinoma (HNSCC). To accurately study novel combination treatments, suitable preclinical mouse models for cetuximab resistance are key yet currently limited. This study aimed to optimize an acquired cetuximab-resistant mouse model, with preservation of the innate immunity, ensuring intact antibody-dependent cellular cytotoxicity (ADCC) functionality. Methods: Cetuximab-sensitive and acquired-resistant HNSCC cell lines, generated in vitro, were subcutaneously engrafted in Rag2 knock-out (KO), BALB/c Nude and CB17 Scid mice with/without Matrigel or Geltrex. Once tumor growth was established, mice were intraperitoneally injected twice a week with cetuximab for a maximum of 3 weeks. In addition, immunohistochemistry was used to evaluate the tumor and its microenvironment. Results: Despite several adjustments in cell number, cell lines and the addition of Matrigel, Rag2 KO and BALB/C Nude mice proved to be unsuitable for xenografting our HNSCC cell lines. Durable tumor growth of resistant SC263-R cells could be induced in CB17 Scid mice. However, these cells had lost their resistance phenotype in vivo. Immunohistochemistry revealed a high infiltration of macrophages in cetuximab-treated SC263-R tumors. FaDu-S and FaDu-R cells successfully engrafted into CB17 Scid mice and maintained their sensitivity/resistance to cetuximab. Conclusion: We have established in vivo HNSCC mouse models with intact ADCC functionality for cetuximab resistance and sensitivity using the FaDu-R and FaDu-S cell lines, respectively. These models serve as valuable tools for investigating cetuximab resistance mechanisms and exploring novel drug combination strategies.

High Infiltration of CD163-Positive Macrophages in Intratumor Compartment Predicts Poor Prognosis in Patients With Upper Urinary Tract Urothelial Carcinoma and Radical Nephroureterectomy.

To investigate the prognostic value of CD68- and CD163-positive macrophages in patients with upper urinary tract urothelial carcinoma (UTUC). This retrospective study enrolled 50 patients (34 men and 16 women) with UTUC who received radical nephroureterectomy (RNU). We evaluated the expression of CD68 and CD163 in the intratumor compartment by immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and bladder recurrence-free survival (BRFS). High infiltration of CD163-positive macrophages in patients with UTUC was significantly correlated with worse OS, CSS, and RFS (P < .05 for all). Multivariate analysis showed that high infiltration of CD163-positive macrophages was an independent negative prognostic factor of OS and CSS in patients with UTUC who received RNU. Lymphovascular invasion was an independent negative prognostic factor of RFS, and high infiltration of CD68-positive macrophages was an independent positive prognostic factor of BRFS. This study indicated that high infiltration of CD163-positive macrophages in the intratumor compartment might be a useful prognostic marker for survival in patients with UTUC who receive RNU. Further, high infiltration of CD68-positive macrophages in the intratumoral compartment might be a useful prognostic marker for bladder recurrence in these patients.

Role of exosome-mediated molecules SNORD91A and SLC40A1 in M2 macrophage polarization and prognosis of ESCC

BackgroundExosome-mediated interaction serves as a significant regulatory factor for M2 macrophage polarization in cancer.MethodsAll accessible data were acquired from The Cancer Genome Atlas (TCGA) database and analyzed using R software. Molecules implicated in exocrine secretion were amassed from the ExoCarta database. Our research initially quantified the immune microenvironment in Esophageal Squamous Cell Carcinoma (ESCC) patients based on the expression profile sourced from the TCGA database. Additionally, we delved into the biological role of M2 macrophages in ESCC via Gene Set Enrichment Analysis (GSEA).ResultsWe observed that patients with high M2 macrophage infiltration typically have a poorer prognosis. Subsequently, a total of 1457 molecules were identified, with 103 of these molecules believed to function through exocrine mechanisms, as supported by data from the ExoCarta database. SNORD91A and SLC40A1 were ultimately pinpointed due to their correlation with patient prognosis. Moreover, we investigated their potential roles in ESCC, including biological enrichment, immune infiltration, and genomic instability analysis.ConclusionsOur study identified exosome-associated molecules, namely SNORD91A and SLC40A1, which notably impact ESCC prognosis and local M2 macrophage recruitment, thereby presenting potential therapeutic targets for ESCC.

NR4A1 as a potential therapeutic target in colon adenocarcinoma: a computational analysis of immune infiltration and drug response.

Background: Colon adenocarcinoma (COAD) is a common malignancy with high morbidity and mortality rates. The immune system plays a crucial role in CRC development and progression, making it a potential therapeutic target. In this study, we analyzed transcriptomic data from CRC patients to investigate immune infiltration and identify potential therapeutic targets. Method and results: we used CIBERSORT to analyze the immune infiltration in COAD samples and found that the high infiltration of M2 macrophages and neutrophils was associated with poor prognosis. Next, we identified NR4A1 as a potential therapeutic target based on its protective effect in two predict models. Using cancer therapeutics response analysis, we found that high expression levels of NR4A1 were sensitive to OSI-930, a tyrosine kinase inhibitor with anti-tumor effects. Conclusion: Our findings suggest that targeting NR4A1 with OSI-930 may be a promising therapeutic strategy for COAD patients with high levels of immune infiltration. However, further studies are needed to investigate the clinical efficacy of this approach.

The expression profiles of signature genes from CD103+LAG3+ tumour-infiltrating lymphocyte subsets predict breast cancer survival.

Tumour-infiltrating lymphocytes (TILs), including T and B cells, have been demonstrated to be associated with tumour progression. However, the different subpopulations of TILs and their roles in breast cancer remain poorly understood. Large-scale analysis using multiomics data could uncover potential mechanisms and provide promising biomarkers for predicting immunotherapy response. Single-cell transcriptome data for breast cancer samples were analysed to identify unique TIL subsets. Based on the expression profiles of marker genes in these subsets, a TIL-related prognostic model was developed by univariate and multivariate Cox analyses and LASSO regression for the TCGA training cohort containing 1089 breast cancer patients. Multiplex immunohistochemistry was used to confirm the presence of TIL subsets in breast cancer samples. The model was validated with a large-scale transcriptomic dataset for 3619 breast cancer patients, including the METABRIC cohort, six chemotherapy transcriptomic cohorts, and two immunotherapy transcriptomic cohorts. We identified two TIL subsets with high expression of CD103 and LAG3 (CD103+LAG3+), including a CD8+ T-cell subset and a B-cell subset. Based on the expression profiles of marker genes in these two subpopulations, we further developed a CD103+LAG3+ TIL-related prognostic model (CLTRP) based on CXCL13 and BIRC3 genes for predicting the prognosis of breast cancer patients. CLTRP-low patients had a better prognosis than CLTRP-high patients. The comprehensive results showed that a low CLTRP score was associated with a high TP53 mutation rate, high infiltration of CD8 T cells, helper T cells, and CD4 T cells, high sensitivity to chemotherapeutic drugs, and a good response to immunotherapy. In contrast, a high CLTRP score was correlated with a low TP53 mutation rate, high infiltration of M0 and M2 macrophages, low sensitivity to chemotherapeutic drugs, and a poor response to immunotherapy. Our present study showed that the CLTRP score is a promising biomarker for distinguishing prognosis, drug sensitivity, molecular and immune characteristics, and immunotherapy outcomes in breast cancer patients. The CLTRP could serve as a valuable tool for clinical decision making regarding immunotherapy.

NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis

BackgroundMacrophages are involved in various immune inflammatory disease conditions. This study aimed to investigate the role and mechanism of macrophages in regulating acute intestinal injury in neonatal necrotizing enterocolitis (NEC).MethodsCD68, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3), cysteine aspartate-specific protease-1 (caspase-1), and interleukin-1β (IL-1β) in paraffin sections of intestinal tissues from NEC and control patients were detected with immunohistochemistry, immunofluorescence, and western blot. Hypertonic pet milk, hypoxia and cold stimulation were used to establish a mouse (wild type and Nlrp3−/−) model of NEC. The mouse macrophage (RAW 264.7) and rat intestinal epithelial cell-6 lines were also cultured followed by various treatments. Macrophages, intestinal epithelial cell injuries, and IL-1β release were determined.ResultsCompared to the gut “healthy” patients, the intestinal lamina propria of NEC patients had high macrophage infiltration and high NLRP3, caspase-1, and IL-1β levels. Furthermore, in vivo, the survival rate of Nlrp3−/− NEC mice was dramatically improved, the proportion of intestinal macrophages was reduced, and intestinal injury was decreased compared to those of wild-type NEC mice. NLRP3, caspase-1, and IL-1β derived from macrophages or supernatant from cocultures of macrophages and intestinal epithelial cells also caused intestinal epithelial cell injuries.ConclusionsMacrophage activation may be essential for NEC development. NLRP3/caspase-1/IL-1β cellular signals derived from macrophages may be the underlying mechanism of NEC development, and all these may be therapeutic targets for developing treatments for NEC.