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PubMed2004

Chemokine-protease interactions in cancer.

Solid tumour and leukemic cells expressing chemokine receptors, metastasize to chemokine-secreting organs. Chemokines indirectly affect tumour development by attracting immunocompetent cells with pro- or anti-tumoral activities. Various membrane-associated and soluble proteases selectively cleave specific chemokines. Precursor plasma chemokines (CXCL7, CCL14) need to be proteolytically processed to obtain receptor affinity. Angiogenic CXC chemokines (CXCL1, CXCL8) have increased CXCR1/CXCR2 affinity after limited NH2-terminal processing, whereas truncated angiostatic chemokines (CXCL10) show lower CXCR3 affinity without loss of angiostatic potential. NH2-terminally cleaved monocyte chemotactic proteins (CCL2, CCL7, CCL8) have impaired capacity to attract tumour-associated macrophages and function as receptor antagonists for intact CC chemokines. Migration of Th1/CCR5+ and Th2/CCR4+ effector lymphocytes toward CCR5 (CCL5, CCL3L1) and CCR4 (CCL22) ligands is affected by cleavage. Although proteolytical processing of chemokines is well studied in vitro, the direct or indirect effects on tumour invasion and metastasis are only poorly evaluated.

Chemokines, CXC↗
PubMed2006

Effect of ultrafine carbon black particles on lipoteichoic acid-induced early pulmonary inflammation in BALB/c mice.

We studied the interaction effects of a single intratracheal instillation of ultrafine carbon black (CB) particles and staphylococcal lipoteichoic acid (LTA) on early pulmonary inflammation in male BALB/c mice. We examined the cellular profile, cytokine and chemokine levels in the bronchoalveolar lavage (BAL) fluid, and expression of chemokine and toll-like receptor (TLR) mRNAs in lungs. LTA produced a dose-related increase in early pulmonary inflammation, which was characterized by (1) influx of polymorphonuclear neutrophils (PMNs) and (2) induction of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha/CCL3, but no effect on monocyte chemoattractant protein (MCP)-1/CCL2 at 24 h after instillation. Levels of some proinflammatory indicators and TLR2-mRNA expression were significantly increased by 14 nm or 95 nm CB (125 microg) and low-dose LTA (10 microg) treatment compared to CB or LTA alone at 4 h after instillation. Notably, PMN levels and production of IL-6 and CCL2 in the 14 nm CB + LTA were significantly higher than that of 95 nm CB + LTA at 4 h after instillation. However, at 24 h after instillation, only PMN levels were significantly higher in the 14 nm CB + LTA than 95 nm CB + LTA but not the cytokines and chemokines. These data show additive as well as synergistic interaction effects of 14 nm or 95 nm ultrafine CB particles and LTA. We suggest that early pulmonary inflammatory responses in male BALB/c mice may be induced in a size-specific manner of the CB particles used in our study.

Animals↗
PubMed2005

Detection of up-regulated genes in thrombin-stimulated human umbilical vein endothelial cells.

INTRODUCTION: Thrombin, a serine protease, plays an important role in such actions as coagulation, cell proliferation and inflammation. It has been sporadically reported that endothelial cells, when stimulated by thrombin via protease-activated receptors (PAR), express various mediators and proteins including cytokines, chemokines, growth factors, and adhesion molecules. However, the pleiotropic effect of thrombin on endothelial cells has not yet been fully elucidated. MATERIALS AND METHODS: We newly searched for the up-regulated genes in the thrombin-stimulated endothelial cells by thorough screening using a microarray chip, printed with 22,575 human genes, followed by verification using real-time PCR (n=3). RESULTS AND CONCLUSIONS: Twelve genes, which were 4.8 times or more up-regulated in a microarray analysis, were selected and further analyzed. In real-time PCR, ICAM-1, IL-8, BIRC3, COL3A1, CXCL3, and CXCL1 were significantly up-regulated in the thrombin-stimulated cells: 16.0-, 8.81-, 5.92-, 3.74-, 1.74-, and 1.66-fold, respectively. VCAM-1, CXCL2, CCL20, CSF2, CD69, and CCL2 were up-regulated in the thrombin-stimulated cells: 12.2-, 2.44-, 1.90-, 1.82-, 1.62-, and 1.06-fold, respectively, without attaining statistical significance. We demonstrated, for the first time, that BIRC3 (anti-apoptotic protein), COL3A1 (matrix protein synthesis), and CXCL3 (chemokine) were up-regulated in the thrombin-stimulated HUVECs.

Baculoviral IAP Repeat-Containing 3 Protein↗
PubMed2005

Comparison of hardwood and softwood dust-induced expression of cytokines and chemokines in mouse macrophage RAW 264.7 cells.

Numerous epidemiological studies have shown that occupational exposure to wood dust can induce several respiratory diseases such as allergic rhinitis, chronic bronchitis, asthma, and sino-nasal adenocarcinoma. However, comparison of the harmful potential of different wood dust species on the basis of epidemiological studies is complicated because in the occupational environment workers are usually exposed to several wood dust species simultaneously. In the present study, we have characterized and compared the effects of two hardwood dusts, beech and teak, and two softwood dusts, pine and spruce, on cytokine and chemokine expression utilizing an in vitro model, murine macrophage cell line RAW 264.7. The expression patterns of selected cytokines and chemokines were assessed by real-time quantitative PCR and by ELISA. All the tested hardwood and softwood dusts induced TNF-alpha expression and inhibited IL-1beta expression. Similarly, all the wood dusts induced the expression of CCL2, CCL3, CCL4, and CXCL2/3 chemokines and inhibited CCL24 expression. Our results indicate that both hardwood and softwood dusts influence the cytokine and chemokine expression of RAW 264.7 cells. Although some differences could be detected in the magnitude of responses to different wood dust species, the two tested wood dust groups, hardwoods and softwoods, have quite similar effects on cytokine and chemokine expression in RAW 264.7 cell line.

Animals↗
PubMed2006

Up-regulation of osteopontin, chemokines, adhesion molecule, and heat shock proteins in 1-hour biopsy from cardiac death donor kidneys.

AIMS: Since April 1979, 471 kidneys were retrieved from donors after cardiac death (DCD) using an in situ regional cooling technique, with excellent renal function and good long-term graft survival. However, the precise cascade of events following transplantation of DCD kidneys and the influence of ischemia-reperfusion injury remain unclear. In this study, we performed gene expression profiling using 1-hour biopsy samples from DCD kidneys versus those from living sources. METHODS: All kidney grafts were procured at our center using an in situ regional cooling technique from DCD. Living donor kidneys (LD) were harvested by open nephrectomy. All graft biopsies were performed 1 hour after reperfusion (DCD n = 8, LD n = 9). We analyzed the expression profile of 20,173 genes. RESULTS: One hundred seventy eight genes were up-regulated (>2-fold difference and DCD/LD > 1.5) and 120 down-regulated (<1/2-fold and LD/DCD > 1.5) in DCD kidneys. Expression of osteopontin (22.5 +/- 2.6-fold DCD vs 7.7 +/- 1.7 LD; P < .001), chemokines (CCL4 4.4 +/- 0.7 vs 2.5 +/- 0.3; P < .01), (CCL2 6.0 +/- 1.3 vs 2.8 +/- 0.5), CXCL1 (9.5 +/- 0.4 vs 2.0 +/- 0.2), and CXCL2 (16.7 +/- 5.3 vs 4.8 +/- 1.3; P < .05), adhesion molecule (ICAM-1 4.7 +/- 0.7 vs 2.5 +/- 0.4; P < .05), and heat shock proteins (HSPA1L 6.7 +/- 0.7 vs 1.6 +/- 0.3, HSPA1A 17.7 +/- 2.6 vs 2.4 +/- 0.5, HSPA1B 13.3 +/- 0.2 vs 3.0 +/- 0.7, HSPA5 6.7 +/- 0.8 vs 3.2 +/- 0.3, HSPB1 2.9 +/- 0.2 vs 1.0 +/- 0.1, and HSPH1 19.4 +/- 3.0 vs 5.9 +/- 1.1; P < .001) were up-regulated in the kidneys from DCD. CONCLUSION: This report analyzed global gene expression using 1-hour biopsy samples from DCD kidneys. These results may provide new insight into the identification of novel target genes for the development of therapeutic approaches and for determining graft viability of kidneys from DCD.

Biopsy↗
PubMed2005

Vaccine-induced cytokine responses in a guinea pig model of pulmonary tuberculosis.

Guinea pigs exposed to very small numbers of virulent tubercle bacilli by the respiratory route develop a disease which mimics many of the important features of the pathogenesis of human tuberculosis (TB), including the expression of strong protective immunity following vaccination with BCG. In order to elucidate the precise immunological mechanisms of vaccine-induced resistance in this model, both mRNA and protein assays for several guinea pig cytokines and chemokines have been developed. The coordinated expression of cytokine and chemokine mRNA and protein was examined in various leukocyte populations and in inflammatory cells and fluid collected following the induction of tuberculous pleurisy in BCG-vaccinated guinea pigs. Real-time RT-PCR assays revealed that the mRNA levels for IFNgamma, TNFalpha, and IL-8 rose over the first few days of TB pleuritis and then declined over the 9 days of the study. Injection of anti-TGFbeta on day 8 following pleurisy induction resulted in significant changes in cytokine mRNA levels and PPD-induced proliferation in pleural effusion lymphocytes taken 24h later. BCG vaccination induced significantly higher levels of bioactive TNFalpha protein in the supernatants of alveolar, peritoneal and splenic cells from BCG-vaccinated guinea pigs cultured in the presence of attenuated or virulent mycobacteria. In sharp contrast, following virulent challenge, all three cell types from BCG-vaccinated guinea pigs produced significantly less TNFalpha. Thus, BCG vaccination appears to modulate the potentially harmful effects of TNFalpha in this model of pulmonary TB. Levels of mRNA for IL-12p40 were upregulated by exposure of infected and uninfected macrophages to recombinant guinea pig (rgp)TNFalpha. The intracellular survival of mycobacteria was enhanced when endogeous TNFalpha activity was neutralized with anti-rgpTNFalpha antiserum. rgp RANTES (CCL5) upregulated mRNA levels for TNFalpha, IL-1beta, MCP-1 (CCL2), and IL-8 (CXCL8) in alveolar and peritoneal macrophages. These results illustrate the profound effects of prior vaccination with BCG on the cytokine and chemokine responses of distinct cell populations in the guinea pig following exposure to attenuated and virulent strains of M. tuberculosis.

Animals↗
PubMed2005

The MCV MC159 protein inhibits late, but not early, events of TNF-α-induced NF-κB activation.

Tumor necrosis factor (TNF-alpha) triggers biphasic activation of the NF-kappaB transcriptional regulator. This process consists of an initial, IkappaBalpha-mediated transient phase and a later, persistent phase dependent on IkappaBbeta degradation. To presumably interfere with the fulfillment of this immunity-associated event in cells infected with the molluscum contagiosum virus (MCV), this pathogen produces the intracellular MC159 protein. To define the mode of action of MC159, the impact of TNF-alpha on HEK 293T cells ectopically expressing the MC159 protein was examined. In this regard, TNF-alpha-induced expression of an NF-kappaB-regulated luciferase reporter gene was partially inhibited by the MC159 protein. This ability was attributed to blockage of the persistent phase of TNF-alpha-induced NF-kappaB activation for the following reasons: (1) the initial phase of NF-kappaB transcriptional activation was not affected by the MC159 protein; (2) the MC159 protein inhibited TNF-alpha-directed degradation of IkappaBbeta, but not IkappaBalpha; and (3) expression of the late NF-kappaB-regulated cell genes, TNF-alpha and CCL2, was decreased in the presence of the MC159 protein while transcription of the early NF-kappaB-regulated cell gene, CXCL1, was not altered. Previously reported MC159-RIP interactions appear to be irrelevant for the MC159 inhibitory function. In contrast, MC159-TRAF2 associations are more relevant for inhibitory function since mutant MC159 proteins unable to bind TRAF2 also cannot inhibit TNF-mediated NF-kappaB activation. In vivo, the MC159 protein may act to prolong virus survival by preventing the infected cell from responding to TNF-alpha, ultimately preventing the cellular production of proinflammatory and immunoattractant molecules.

Cell Line↗
PubMed2006

Modulatory effects of Echinacea purpurea extracts on human dendritic cells: a cell- and gene-based study.

Echinacea spp. are popularly used as an herbal medicine or food supplement for enhancing the immune system. This study shows that plant extracts from root [R] and stem plus leaf [S+L] tissues of E. purpurea exhibit opposite (enhancing vs inhibitory) modulatory effects on the expression of the CD83 marker in human dendritic cells (DCs), which are known as professional antigen-presenting cells. We developed a function-targeted DNA microarray system to characterize the effects of phytocompounds on human DCs. Down-regulation of mRNA expression of specific chemokines (e.g., CCL3 and CCL8) and their receptors (e.g., CCR1 and CCR9) was observed in [S+L]-treated DCs. Other chemokines and regulatory molecules (e.g., CCL4 and CCL2) involved in the c-Jun pathway were found to be up-regulated in [R]-treated DCs. This study, for the first time, demonstrates that E. purpurea extracts can modulate DC differentiation and expression of specific immune-related genes in DCs.

Antigens, CD↗
PubMed2004

The innate pulmonary granuloma: characterization and demonstration of dendritic cell recruitment and function.

Granulomas are innate sequestration responses that can be modified by superimposed acquired immune mechanisms. The present study examined the innate stage of pulmonary granuloma responses to bead-immobilized Th1- and Th2-inducing pathogen antigens (Ags), Mycobacteria bovis purified protein derivative (PPD) and Schistosoma mansoni soluble egg Ags (SEA). Compared to a nonpathogen Ag, PPD and SEA bead elicited larger lesions with the former showing accelerated inflammation. Temporal analyses of cytokine and chemokine transcripts showed all Ag beads induced tumor necrosis factor-alpha mRNA but indicated biased interleukin (IL)-1, IL-6, and IL-12 expression with PPD challenge. All beads elicited comparable levels of CXCL9, CXL10, CCL2, CCL17, and CCL22 mRNA, but PPD beads caused biased CXCL2 CXCL5, CCL3, and CCL4 expression whereas both pathogen Ags induced CCL7. Immunohistochemical, electron microscopic, and flow cytometric analyses showed that Ag beads mobilized CD11c+ dendritic cells (DCs) of comparable maturation. Transfer of DCs from PPD Ag-challenged lungs conferred a Th1 anamnestic cytokine response in recipients. Surprisingly, transfer of DCs from the helminth SEA-challenged lungs did not confer the expected Th2 response, but instead rendered recipients incapable of Ag-elicited IL-4 production. These results provide in vivo evidence that lung DCs recruited under inflammatory conditions favor Th1 responses and alternative mechanisms are required for Th2 commitment.

Animals↗
PubMedDate not supplied

Formation and decomposition of chloroaromatic compounds in chlorine-containing benzene/oxygen flames.

Premixed chlorine-containing, fuel-rich, low-pressure benzene/oxygen flames were analysed for the formation of (oxygenated) chloroaromatic compounds and their radicals by means of the condensation/radical-scavenging method (Hausmann, M., Homann, K.-H., 1995. Ber. Busenges. Phys. Chem. 99, 853-862). Several chlorinated organic compounds (methyl chloride, t-butyl chloride, chlorobenzene, chloroform) were used as additives within a maximum concentration of 10% of total fuel. Product identification and quantification were performed by GC/MS. The extent of formation of chloroaromatic compounds in these flames was largest in the cases of chlorobenzene and chloroform as additives. For chlorobenzene, 12 different chloroaromatics could be analysed in between C7H7Cl and C12H9Cl. Their formation is mainly due to conversion of initial chlorobenzene into substituted or oxidised derivatives, or growth products. Additional chlorination of aromatics is shown to be of minor importance in chlorobenzene-containing flames. Three isomeric (o/m/p) scavenging products could be identified for the chlorophenyl radical. In the chloroform case, 15 chloroaromatics could be analysed in between C6H5Cl and C14H9Cl. The weak C-Cl bond in chloroform is responsible for the high extent of chloroaromatics formation, either by Cl abstraction from the additive or by chlorination reactions via Cl radicals. Additionally, specific pathways to (di)chloroaromatics and chlorinated fulvene-type structures are outlined via CHCl2 and CCl2 radicals.

Journal Article↗
PubMed2004

Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact on the development of humoral immunity.

Mice lacking CD38, an ectoenzyme that generates the calcium-mobilizing metabolite cADPR, make reduced T cell-dependent antibody responses. Despite the predicted role for CD38 in B cell activation, we find that CD38 regulates the migration of dendritic cell (DC) precursors from the blood to peripheral sites and controls the migration of mature DCs from sites of inflammation to lymph nodes. Thus, T cells are inefficiently primed in Cd38(-/-) mice, leading to poor humoral immune responses. We also show that CD38 and cADPR modulate calcium mobilization in chemokine-stimulated DCs and are required for the chemotaxis of immature and mature DCs to CCL2, CCL19, CCL21, and CXCL12. Therefore, CD38 regulates adaptive immunity by controlling chemokine receptor signaling in DCs.

ADP-ribosyl Cyclase↗
PubMed1989

Recognition of beta beta'-substituted and alpha beta,alpha'beta'-disubstituted phosphonate analogues of bis(5'-adenosyl) tetraphosphate by the bis(5'-nucleosidyl)-tetraphosphate pyrophosphohydrolases from Artemia embryos and Escherichia coli.

A total of 13 phosphonate analogues of bis(5'-adenosyl) tetraphosphate (AppppA) have been tested as substrates and inhibitors of the asymmetrically cleaving bis(5'-nucleosidyl) tetraphosphatase (NppppNase) from Artemia and the symmetrically cleaving NppppNase from Escherichia coli. With the Artemia enzyme, the substrate efficiency of beta beta'-substituted compounds decreased with decreasing substituent electronegativity (O greater than CF2 greater than CHF greater than CCl2 greater than CHCl greater than CH2) such that AppCF2ppA and AppCH2ppA were hydrolyzed at 70% and 2.5% of the rate of AppppA, respectively. These compounds were competitive inhibitors of this enzyme with Ki values that generally also decreased with electronegativity from 12 microM for AppCF2ppA to 0.4 microM for AppCH2ppA (Km for AppppA = 33 microM). AppCH = CHppA and AppCH2CH2ppA were neither effective substrates nor inhibitors of the Artemia enzyme. Alpha beta,alpha'beta'-Disubstituted analogues were generally less effective inhibitors with Ki values ranging from 23 microM (ApCH2ppCH2pA) to greater than 1.5 mM (ApCH2CH2ppCH2CH2pA). However, they displayed a low and unexpected rate of symmetrical cleavage by the Artemia enzyme: e.g., ApCHFppCHFpA yielded ApCHFp at 3% of the rate of AppppA breakdown. Both sets of analogues were also competitive inhibitors of the E. coli NppppNase with Ki values ranging from 7 microM (AppCH2ppA) to 250 microM (ApCH2CH2ppCH2CH2pA) (Km for AppppA = 28 microM). The only alpha beta,alpha'beta'-disubstituted analogue to be hydrolyzed by the E. coli enzyme was ApCF2ppCF2pA at 0.2% of the rate of AppppA; however, several of the beta beta'-substituted compounds showed a limited degree of asymmetrical cleavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Anhydride Hydrolases↗
PubMed2001

A new hydrate-based recovery process for removing chlorinated hydrocarbons from aqueous solutions.

The main objective of this study was to check the feasibility of the newly proposed hydrate-based chlorinated hydrocarbon (CHC) recovery process for removing chlorinated hydrocarbons from aqueous solutions. Two key process variables of hydrate phase equilibria and formation kinetics were closely examined to develop the overall conceptual design of this technology. First, the ternary four-phase (H-LW-LCHC-V) hydrate equilibria of aqueous solutions containing methylene chloride (CH2Cl2), carbon tetrachloride (CCl4), 1,2-dichloroethane (CH2ClCH2Cl), 1,1,1-trichloroethane (CH3CCl3), and 1,1-dichloroethylene (CH2= CCl2) were measured at various temperature and pressure conditions using three different types of help gases (CO2, N2, CH4). The help gas + water + chlorinated hydrocarbons systems greatly reduced the hydrate-forming pressure, which confirmed the mixed hydrates with chlorinated hydrocarbons more stabilized than the simple hydrates consisting of a help gas and water. The degree of stabilization was found to follow the order of 1,2-dichloroethane < 1,1-dichloroethylene < methylene chloride < 1,1,1-trichloroethane < carbon tetrachloride. For the N2 + water + carbon tetrachloride system, the formation pressure reduction as much as 96% was observed at 279.35 K. Second, the formation kinetic experiments of carbon dioxide hydrates containing chlorinated hydrocarbons were conducted under isothermal and isobaric conditions. The consumption rate of carbon dioxide gas became fast at the early time of the growth period, gradually decreased, and finally went to the complete hydration. The proposed hydrate-based recovery process appears to be very simple from the operational point of view because no special facilities requiring sensitive and complex function are needed. Another advantage is that this process only requires carbon dioxide as a hydrate former. Best of all, this process can be applied to separation and recovery of other organic pollutants dissolved in aqueous solutions without changing the basic concept.

Carbon Dioxide↗
PubMed2005

Dichlorocarbene addition to cyclopropenes: a computational study.

Reaction paths for addition of dichlorocarbene to 1,2-disubstituted cyclopropenes were calculated using hybrid density functional theory (B3LYP/6-31G) in the gas phase and in the presence of a continuum solvation model corresponding to acetonitrile. In both the gas phase and acetonitrile, :CCl2-cyclopropene addition follows an asymmetric, non-least-motion approach. Barriers to addition range from 0 to 2 kcal/mol. The reactions proceed in concerted fashion in both the gas phase and solution to yield 1,3-dienes or bicyclobutanes. The reaction pathway on this complex potential energy surface of this reaction appears to bifurcate, and the product distribution is believed to be controlled by reaction dynamics. At the present level of theory, there appears to be no minimum on the potential energy surface corresponding to a dipolar intermediate.

Computer Simulation↗
PubMed2005

Pentachlorocyclopropane/base complexes: matrix isolation infrared spectroscopic and density functional study of C-H- - -N hydrogen bonds.

Hydrogen-bonded complexes of pentachlorocyclopropane with the bases acetonitrile, ammonia, monomethylamine, and dimethylamine have been isolated and characterized for the first time in argon matrices at 16 K. Coordination of the proton of pentachlorocyclopropane (Pccp) to the electron donor (N) of the base was evidenced by red shifts of the CH stretching mode. These shifts, which range from 22 to 170 cm(-1), increase in the order CH3CN, NH3, (CH3)NH2, and (CH3)2NH. Density functional theory (DFT) calculations at the B3LYP level agree well with experiment and support the formation of 1:1 complexes of Pccp/base. Distinct changes were observed in ring modes as well as CCl and CCl2 modes. The hydrogen bond energy of the complexes varies from 2.95 to 4.22 kcal/mol and is stronger than our previously studied bromocyclopropane-ammonia complex (2.35 kcal/mol, MP2).

Journal Article↗
PubMed2005

Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis.

Ligation of the chemokine receptor CCR2 on monocytes and macrophages with its ligand CCL2 results in activation of the cascade consisting of phosphatidylinositol-3-OH kinase (PI(3)K), the small G protein Rac and lamellipodium protrusion. We show here that a unique clathrin heavy-chain repeat homology protein, FROUNT, directly bound activated CCR2 and formed clusters at the cell front during chemotaxis. Overexpression of FROUNT amplified the chemokine-elicited PI(3)K-Rac-lamellipodium protrusion cascade and subsequent chemotaxis. Blocking FROUNT function by using a truncated mutant or antisense strategy substantially diminished signaling via CCR2. In a mouse peritonitis model, suppression of endogenous FROUNT markedly prevented macrophage infiltration. Thus, FROUNT links activated CCR2 to the PI(3)K-Rac-lamellipodium protrusion cascade and could be a therapeutic target in chronic inflammatory immune diseases associated with macrophage infiltration.

Amino Acid Sequence↗
PubMed2026

FAP+ pericyte-like cells promote monocyte differentiation into tumor-associated macrophages in glioblastoma.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by profound immunosuppression that facilitates tumor progression and promotes therapeutic resistance. Fibroblast activation protein (FAP), a recognized theranostic target in multiple cancers, is upregulated in GBM and predominantly expressed by pericyte-like stromal cells. Here we identify a role for FAP&#x207a; pericyte-like cells in shaping the GBM immune microenvironment through monocyte recruitment and differentiation. Analysis of The Cancer Genome Atlas (TCGA) datasets, supported by reverse-transcription quantitative PCR and immunohistochemistry, revealed that elevated FAP expression-serving as a proxy for the abundance of FAP&#x207a; pericyte-like cells-is associated with an immune-enriched tumor microenvironment characterized by higher macrophage abundance and elevated expression of M2 polarization markers. Spatial analyses, including immunofluorescence and spatial transcriptomics, demonstrated that immunosuppressive macrophages preferentially localize in proximity to FAP&#x207a; pericytes. Single-cell RNA sequencing identified these FAP&#x207a; cells as a distinct perivascular stromal subset with a unique expression pattern of extracellular matrix components and cytokines, including CCL2 and CSF1, with corresponding receptors expressed on myeloid cells. Functional assays using patient-derived FAP&#x207a; pericyte-like cells confirmed their ability to attract monocytes via soluble mediators and to promote their differentiation and polarization into tumor-associated macrophages with immunoregulatory features, partly mediated by the CSF1-CSF1R axis. Orthotopic co-implantation experiments in mice further supported their capacity to enhance myeloid infiltration in vivo. Consistent with these biological effects, a transcriptional signature characteristic of FAP&#x207a; pericytes correlated with worse overall survival in patients with GBM. Together, these findings position FAP&#x207a; pericyte-like cells as modulators of the GBM immune landscape, fostering a tumor-permissive niche by promoting the differentiation of circulating monocytes into immunoregulatory macrophages. Targeting this stromal population may offer new therapeutic avenues to reprogram tumor-associated immune responses in GBM.

Journal Article↗