Tumor-associated macrophage infiltration in meningioma.
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ABSTRACT:
SUBMITTER: Proctor DT
PROVIDER: S-EPMC7212927 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:PurposeTumour-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment and provide a barrier against the cytotoxic effector functions of T cells and natural killer (NK) cells. Recently, TAMs have become increasingly recognised as an attractive target in combination therapy with PD-1/PD-L1 immuno-checkpoint blockades (ICBs). However, the relationship between PD-L1 expression and TAMs remains unknown in nasopharyngeal carcinoma (NPC).Patients and methodsA total of 212 NPC patients from Nanfang hospital were collected in this study. We evaluated the expression of PD-L1 in tumor cells, CD68 (pan-macrophages), and CD163 (M2-like macrophage) in NPC tissues using immunohistochemical (IHC) staining.ResultsThe positivity of PD-L1 on tumor cells was 61.3% (130/212). The infiltration densities of CD68+ cells and CD163+ cells in PD-L1-positive NPC tissues were significantly higher than those in PD-L1-negative NPC tissues (P=0.0012 for CD68; P<0.0001 for CD163). Logistic regression analysis showed that high densities of CD68+ macrophages and CD163+ TAMs were significantly associated with increased PD-L1 expression. Subgroup analyses demonstrated that a positive PD-L1 expression on tumor cells in combination with lower CD163+ TAMs density was significantly associated with favorable prognosis, whereas negative PD-L1 expression on tumor cells with higher CD163+ TAMs density was associated with worse prognosis.ConclusionThe PD-L1 expression in tumor cells was positively correlated with TAMs density in tumor microenvironment of NPC, suggesting TAMs as a new target for combination therapy to improve the response rate of ICBs in NPC treatment.
| S-EPMC7669506 | biostudies-literature
Project description:BackgroundTumor-associated macrophages (TAMs) support growth in most human cancers, with the notable exception of colorectal adenocarcinoma, in which TAM infiltration of primary tumors is correlated with a better outcome. The importance of TAMs in colorectal liver metastases (CLM) is unknown.MethodsUsing a tissue microarray of CLM resected at their institution from 1998 to 2000, the authors quantified immune marker expression by immunohistochemistry (IHC) using Metamorph Image Analysis software. Findings showed that CD68, CD3, CD4, CD8, FoxP3, and MHC-I were correlated with overall survival (OS) and disease-free survival (DFS).ResultsTumor cores from 158 patients were analyzed. The median follow-up period was 117 months for survivors (n = 39). The univariate analysis showed a significant positive association between DFS and CD4+ (p = 0.025) and CD68+ (p = 0.007). The findings showed a significant positive correlation of OS with CD4+ (p = 0.042), whereas the correlation with CD68+ was not significant (p = 0.17). Cutoffs were determined to dichotimize each marker for the highest log-rank statistic. Patients with CD4high had a median OS of 115 months and DFS of 41 months (p = 0.007 compared with 40 and 16 months, respectively, for patients with CD4low (p = 0.022). Patients with CD68high had a median OS of 50 months and a median DFS of 25 months (p = 0.67) compared with 43 and 15 months (p = 0.028). In the multivariate analysis of factors affecting DFS, high CD68 was associated with longer DFS (hazard ratio [HR], 0.63, 95% confidence interval [CI], 0.43-0.94; p = 0.02), independently of clinicopathologic variables and CD4.ConclusionsHigh TAM infiltration in resected CLM is associated with better outcome, independently of known clinicopathologic and immune predictors. This suggests that TAM depletion, which is being tested clinically in other cancers, may be detrimental in CLM.
| S-EPMC5505689 | biostudies-literature
Project description:Tumor microenvironment (TME) plays a particularly important role in the progression, invasion and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the tumor microenvironment in CC. However, the results of studies on the correlation between TAMs and progression in CC are still controversial. This research aimed to investigate the relationship between TAMs infiltration and progression in CC. A total of 100 patients with CC were included in the study. The correlation between TAMs and clinicopathologic features was studied. Besides, a systematic literature search was conducted from legitimate electronic databases to specifically evaluate the role of TAMs in TME of cervical carcinoma. In the meta-analysis, high stromal CD68+ TAMs density was relevant to lymph node metastasis (WMD = 11.89, 95% CI: 5.30-18.47). At the same time, CD163+ M2 TAM density was associated with lymph node metastasis (OR = 2.42, 95% CI: 1.09-5.37; WMD = 39.37, 95% CI: 28.25-50.49) and FIGO stage (WMD = -33.60, 95% CI: -45.04 to -22.16). This was further confirmed in the experimental study of 100 tissues of cervical cancer. It supported a critical role of TAMs as a prospective predictor of cervical cancer. In conclusion, CD68+ TAM and CD163+ M2 TAM infiltration in CC were associated with tumor progression. And CD163+ M2 TAM infiltration was associated with more advanced FIGO stage and lymph node metastasis in CC.
| S-EPMC8493445 | biostudies-literature
Project description:Ovarian cancer (OC) is a frequently lethal gynecologic malignancy, characterized by a poor prognosis and high recurrence rate. The immune microenvironment has been implicated in the progression of OC. We characterized the immune landscape in primary and malignant OC ascites using single-cell and bulk transcriptome raw OC data acquired from the Gene Expression Omnibus and The Cancer Genome Atlas databases. We then used the CIBERSORT deconvolution algorithm, weighted gene co-expression network analysis, univariate and multivariate Cox analyses, and the LASSO algorithm to develop a tumor-associated macrophage-related gene (TAMRG) prognostic signature, which enabled us to stratify and predict overall survival (OS) of OC patients. In addition, inter- and intra-patient heterogeneity of infiltrating immune cells was characterized at single-cell resolution. Tumor-infiltrating macrophages with an M2 phenotype exhibited immunosuppressive activity. M1 macrophages positively correlated with OS, whereas activated mast cells, neutrophils, M2 macrophages, and activated memory CD4+ T cells were all negatively correlated with OS. A total of 219 TAMRGs were identified, and a novel 6-gene signature (TAP1, CD163, VSIG4, IGKV4-1, CD3E, and MS4A7) with independent prognostic value was established. These results show that a TAMRG-based signature may be a promising prognostic and therapeutic target in OC.
| S-EPMC8544311 | biostudies-literature
Project description:Tumor-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, the molecular mechanism underlying the infiltration of TAMs into HCC microenvironment is largely unclear. Recent studies have reported that alteration of mitochondrial nucleoid structures induces mitochondrial DNA (mtDNA) release into the cytosol, which is recognized as mtDNA stress, and consequently regulates innate immunity. Here we aimed to investigate whether mitochondrial fission induces mtDNA stress and then promotes TAM infiltration and HCC progression. Confocal microscopy and real-time PCR were used to detect cytosolic mtDNA content in HCC cells. The relationship between the expression of mitochondrial fission key regulator dynamin-related protein 1 (Drp1) and the percentage of CD163 (a marker of TAMs)-positive cells was investigated in HCC tissues using immunohistochemistry. Finally, the effect of Drp1 overexpression in HCC cells on recruitment and polarization of TAMs was investigated. Our data showed that increased Drp1 expression was positively correlated with the infiltration of TAMs into HCC tissues. Drp1-mediated mitochondrial fission induced the cytosolic mtDNA stress to enhance the CCL2 secretion from HCC cells by TLR9-mediated NF-?B signaling pathway, and thus promoted the TAM recruitment and polarization. Depleting cytosolic mtDNA using DNase I or blocking TLR9 pathway by TLR9 antagonist, siRNA for TLR9 or p65 in HCC cells with Drp1 overexpression significantly decreased the recruitment and polarization of TAMs. Blocking CCR2 by antagonist significantly reduced TAM infiltration and suppressed HCC progression in mouse model. In conclusion, our findings reveal a novel mechanism of TAM infiltration in HCC by mitochondrial fission-induced mtDNA stress.
| S-EPMC6755992 | biostudies-literature
Project description:The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.
| S-EPMC7339942 | biostudies-literature
Project description:BACKGROUND: Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-?B. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. METHODS: Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-?) and low (TNF-?) expression in M2 macrophages, and molecules in NF-?B pathway (IKK? and I?-B) were evaluated by RT-qPCR or western blot. RESULTS: EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-? and increased TNF-?. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKK? suppression and concomitant I-?B accumulation; increase of IL-6 and TGF-?; and, decrease of TNF-?. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-?B pathway elicited by EGCG-treated exosomes. CONCLUSIONS: Our data demonstrate that EGCG up-regulates miR-16 in tumor cells, which can be transferred to TAM via exosomes and inhibits TAM infiltration and M2 polarization. We suggest a novel mechanism by which EGCG exerts anti-tumor activity via regulation of TAM in tumor microenvironment.
| S-EPMC3848851 | biostudies-other
Project description:BackgroundTumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment. Tumor cell-derived spondin 2 (SPON2) is an extracellular matrix glycoprotein that has complicated roles in recruitment of macrophages and neutrophils during inflammation. Overexpression of SPON2 has been shown to promote tumor cell migration in colorectal cancer (CRC). However, the mechanism by which SPON2 regulates the accumulation of TAMs in the tumor microenvironment (TME) of CRC is unknown.MethodsImmunohistochemistry was used to examine SPON2 expression in clinical CRC tissues. In vitro migration assays, transendothelial migration assays (iTEM), and cell adhesion assays were used to investigate the effects of SPON2 on monocyte/macrophage migration. Subcutaneous tumor formation and orthotopic implantation assays were performed in C57 BL/6 mice to confirm the effects of SPON2 on TAM infiltration in tumors.ResultsSPON2 expression is positively correlated with M2-TAM infiltration in clinical CRC tumors and poor prognosis of CRC patients. In addition, SPON2 promotes cytoskeletal remodeling and transendothelial migration of monocytes by activating integrin β1/PYK2 axis. SPON2 may indirectly induce M2-polarization through upregulating cytokines including IL10, CCL2 and CSF1 expression in tumor cells. Blocking M2 polarization and Macrophage depletion inhibited the SPON2-induced tumors growth and invasion. Furthermore, blocking the SPON2/integrin β1/PYK2 axis impairs the transendothelial migration of monocytes and cancer-promoting functions of TAMs in vivo.ConclusionsOur findings demonstrate that SPON2-driven M2-TAM infiltration plays an important role during CRC tumor growth and metastasis. SPON2 may be a valuable biomarker guiding the use of macrophage-targeting strategies and a potential therapeutic target in advanced CRC.
| S-EPMC8477524 | biostudies-literature
Project description:Serine proteases has been considered to be closely associated with the inflammatory response and tumor progression. As a novel serine protease, the biological function of PRSS23 is rarely studied in cancers. In this study, the prognostic significance of PRSS23 was analyzed in two-independent gastric cancer (GC) cohorts. PRSS23 overexpression was clinically correlated with poor prognosis and macrophage infiltration of GC patients. Loss-of-function study verified that PRSS23 plays oncogenic role in GC. RNA-seq, qRT-PCR, western blotting and ELISA assay confirmed that serine protease PRSS23 positively regulated FGF2 expression and secretion. Single-cell analysis and gene expression correlation analysis showed that PRSS23 and FGF2 were high expressed in fibroblasts, and highly co-expressed with the biomarkers of tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and mesenchymal cells. Functional analysis confirmed PRSS23/FGF2 was required for TAM infiltration. Rescue assay further verified that PRSS23 promotes GC progression and TAM infiltration through FGF2. Survival analysis showed that high infiltration of M1-macrophage predicted favorable prognosis, while high infiltration level of M2-macrophage predicted poor prognosis in GC. Our finding highlights that PRSS23 promotes TAM infiltration through regulating FGF2 expression and secretion, thereby resulting in a poor prognosis.
| S-EPMC9520605 | biostudies-literature
Project description:Peripheral T cell lymphoma (PTCL) is an aggressive form of non-Hodgkin's lymphoma characterized by a poor prognosis. In this study, we examined the prognostic value of two T-cell-specific transcription factors, GATA3 and T-bet, in PTCL, uncovered the pathogenesis of PTCL, and investigated new PTCL therapeutic targets. Samples from 109 PTCL patients were examined for expression of GATA3, T-bet and CD68. High GATA3 expression correlated with poor survival in PTCL patients and with tumor-associated macrophage (TAM) infiltration, as indicated by the presence of CD68-positive cells. Multivariate analysis further confirmed that high GATA3 expression and Eastern Cooperative Oncology Group (ECOG) scores higher than 2 were independent predictors of patient survival. Using lentiviral transfection to induce stable GATA3 knockdown in a PTCL cell line, we observed that GATA-3 knockdown in Hut78 cells decreased levels of IL4, IL5, IL13 and VEGF mRNA and reduced the number of co-cultured U937 cells that differentiated towards the M2 phenotype. These results suggest that high GATA3 expression is a predictor of a poor prognosis in PTCL, and that T lymphoma cells promote M2-type macrophage differentiation through a GATA3-dependent mechanism.
| S-EPMC5323155 | biostudies-literature