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Journal For Immunotherapy of Cancer Jun 2024Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and...
BACKGROUND
Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.
METHODS
Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS
EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS
MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
Topics: Animals; Mice; Humans; Matrix Metalloproteinase 9; Macrophages; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Receptors, Cell Surface; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Receptors, Antigen, T-Cell; Tumor Microenvironment; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 38886114
DOI: 10.1136/jitc-2023-008375 -
Clinical Case Reports Jun 2024Chronic myelomonocytic leukemia, a rare case of hematological malignancy mainly affects the elderly and may present with life threatening pericardial effusion as an...
KEY CLINICAL MESSAGE
Chronic myelomonocytic leukemia, a rare case of hematological malignancy mainly affects the elderly and may present with life threatening pericardial effusion as an initial manifestation. High index of suspicion is hence key for early management.
ABSTRACT
We present a case of an 81-year-old African male who presented with progressive cough, respiratory distress and bilateral lower limb swelling, and was diagnosed with life-threatening pericardial effusion resulting from chronic myelomonocytic leukemia following complete blood count, peripheral blood film, bone marrow aspirate with trephine biopsy, and flow cytometry studies.
PubMed: 38855083
DOI: 10.1002/ccr3.9048 -
Skin Health and Disease Jun 2024In the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of...
BACKGROUND
In the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of proinflammatory transcription factors (TFs) and their translocation to the cell's nucleus. Therein, the TFs induce expression of genes encoding mediators of skin inflammation. The Nuclear Transport Checkpoint Inhibitors (NTCIs) were developed to regulate nuclear translocation of activated TFs, the essential step of inflammatory response. This new class of cell-penetrating peptide therapeutics controls inflammation caused by allergic, autoimmune, metabolic, and microbial insults. In preclinical model of AD, the treatment with NTCI, cSN50.1 peptide, suppressed the expression of Thymic Stromal Lymphopoietin (), the key gene in the development of allergic inflammation, among the 15 genes silenced by the NTCI. Here, we report the mechanism of anti-inflammatory action of NTCI in human skin-derived KCs.
OBJECTIVES
We aimed to determine whether the NTCI treatment can protect human KCs from harmful inflammatory insults.
METHODS
Human primary KCs were pretreated with NTCI and challenged with the mix of cytokines Tumour Necrosis Factor alpha (TNF-α) and Interleukin (IL)-17A, or with Phorbol 12-Myristate 13-Acetate (PMA), and analysed for nuclear content of TFs and the expression of genes encoding mediators of inflammation.
RESULTS
The nuclear import of TFs, Nuclear Factor ĸB (NF-ĸB) and Signal Transduction and Activator of Transcription 3 (STAT3), was inhibited in cells treated with NTCI. The expression of along with genes encoding the core mediators of inflammation (, , and ) was suppressed by NTCI. Noteworthy, NTCI silenced genes encoding Granulocyte-Macrophage Colony-Stimulating Factor (), and chemokine IL-8 (), responsible for skin infiltration by the eosinophils and other myelomonocytic cells.
CONCLUSION
The control of inflammatory response in human KCs by NTCI is attributed to the inhibition of nuclear import of proinflammatory TFs. The protection of human KCs by NTCI, adds new perspectives to the completed Phase two clinical trial of the NTCI (AMTX-100 CF) for AD (NCT04313400).
PubMed: 38846687
DOI: 10.1002/ski2.356 -
BMC Cancer May 2024Recent studies have shown that blue light-emitting diode (LED) light has anti-tumor effects, suggesting the possibility of using visible light in cancer therapy....
Recent studies have shown that blue light-emitting diode (LED) light has anti-tumor effects, suggesting the possibility of using visible light in cancer therapy. However, the effects of blue light irradiation on cells in the tumor microenvironment, including tumor-associated macrophages (TAMs), are unknown. Here, THP-1 cells were cultured in the conditioned medium (CM) of HCT-116 cells to prepare TAMs. TAMs were divided into LED-irradiated and control groups. Then, the effects of blue LED irradiation on TAM activation were examined. Expression levels of M2 macrophage markers CD163 and CD206 expression were significantly decreased in LED-irradiated TAMs compared with the control group. While control TAM-CM could induce HCT-116 cell migration, these effects were not observed in cells cultured in TAM-CM with LED irradiation. Vascular endothelial growth factor (VEGF) secretion was significantly suppressed in LED-exposed TAMs. PD-L1 expression was upregulated in HCT-116 cells cultured with TAM-CM but attenuated in cells cultured with LED-irradiated TAM-CM. In an in vivo model, protein expression levels of F4/80 and CD163, which are TAM markers, were reduced in the LED-exposed group. These results indicate that blue LED light may have an inhibitory effect on TAMs, as well as anti-tumor effects on colon cancer cells.
Topics: Humans; Colonic Neoplasms; Tumor-Associated Macrophages; Light; Animals; HCT116 Cells; Mice; Tumor Microenvironment; Cell Movement; Culture Media, Conditioned; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Vascular Endothelial Growth Factor A; Receptors, Cell Surface; Macrophages; Phototherapy; Macrophage Activation; Blue Light
PubMed: 38822331
DOI: 10.1186/s12885-024-12440-1 -
Scientific Reports May 2024The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and...
The effects of low doses of ionizing radiation on atherosclerosis remain uncertain, particularly as regards the generation of pro- or anti-inflammatory responses, and the time scale at which such effects can occur following irradiation. To explore these phenomena, we exposed atheroprone ApoE mice to a single dose of 0, 0.05, 0.5 or 1 Gy of Cs (γ) administered at a 10.35 mGy min dose rate and evaluated short-term (1-10 days) and long-term consequences (100 days). Bone marrow-derived macrophages were derived from mice 1 day after exposure. Irradiation was associated with a significant skewing of M0 and M2 polarized macrophages towards the M2 phenotype, as demonstrated by an increased mRNA expression of Retnla, Arg1, and Chil3 in cells from mice exposed to 0.5 or 1 Gy compared with non-irradiated animals. Minimal effects were noted in M1 cells or M1 marker mRNA. Concurrently, we observed a reduced secretion of IL-1β but enhanced IL-10 release from M0 and M2 macrophages. Effects of irradiation on circulating monocytes were most marked at day 10 post-exposure, when the 1 Gy dose was associated with enhanced numbers of both Ly6C and Ly6 cells. By day 100, levels of circulating monocytes in irradiated and non-irradiated mice were equivalent, but anti-inflammatory Ly6C monocytes were significantly increased in the spleen of mice exposed to 0.05 or 1 Gy. Long term exposures did not affect atherosclerotic plaque size or lipid content, as determined by Oil red O staining, whatever the dose applied. Similarly, irradiation did not affect atherosclerotic plaque collagen or smooth muscle cell content. However, we found that lesion CD68+ cell content tended to decrease with rising doses of radioactivity exposure, culminating in a significant reduction of plaque macrophage content at 1 Gy. Taken together, our results show that short- and long-term exposures to low to moderate doses of ionizing radiation drive an anti-inflammatory response, skewing bone marrow-derived macrophages towards an IL-10-secreting M2 phenotype and decreasing plaque macrophage content. These results suggest a low-grade athero-protective effect of low and moderate doses of ionizing radiation.
Topics: Animals; Macrophages; Plaque, Atherosclerotic; Mice; Cesium Radioisotopes; Apolipoproteins E; Gamma Rays; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Atherosclerosis; Male; Mice, Knockout; CD68 Molecule
PubMed: 38816571
DOI: 10.1038/s41598-024-63084-x -
Haematologica May 2024Not available.
Not available.
PubMed: 38813703
DOI: 10.3324/haematol.2024.285326 -
Scientific Reports May 2024Telocytes are a unique interstitial cell type that functions in adulthood and embryogenesis. They have characteristic immunohistochemical phenotypes while acquiring...
Telocytes are a unique interstitial cell type that functions in adulthood and embryogenesis. They have characteristic immunohistochemical phenotypes while acquiring different immunohistochemical properties related to the organ microenvironment. The present study aims to investigate the immunohistochemical features of embryonic telocytes during myogenesis and describe their morphology using light microscopy and TEM. Telocytes represent a major cellular constituent in the interstitial elements. They had distinguished telopodes and podoms and formed a 3D interstitial network in the developing muscles. They formed heterocellular contact with myoblasts and nascent myotubes. Telocytes also had distinctive secretory activity. Telocytes identified by CD34. They also express CD68 and MMP-9 to facilitate the development of new tissues. Expression of CD21 by telocytes may reveal their function in immune defense. They also express VEGF, which regulates angiogenesis. In conclusion, the distribution and immunological properties of telocytes in the myogenic tissue indicate that telocytes provide biological and structural support in the development of the myogenic tissue architecture and organization.
Topics: Telocytes; Animals; Muscle Development; Immunohistochemistry; Mice; Antigens, CD; Antigens, CD34; Cellular Microenvironment; Matrix Metalloproteinase 9; Antigens, Differentiation, Myelomonocytic; Vascular Endothelial Growth Factor A; Myoblasts
PubMed: 38802438
DOI: 10.1038/s41598-024-62103-1 -
Frontiers in Immunology 2024levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. can be produced by Th17 cells and locally within joints by tissue-resident...
OBJECTIVES
levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. can be produced by Th17 cells and locally within joints by tissue-resident cells. induces osteoblast mineralization . As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of in spondyloarthritis.
METHODS
Serum, peripheral blood mononuclear cells ( = 15-35) and synovial tissue ( = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR.
RESULTS
Synovial tissue of axSpA patients shows significantly more -positive cells than that of HCs ( < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs ( < 0.001 and < 0.01). However, peripheral blood CD4 T cells from axSpA and PsA patients show higher positivity for in the PrimeFlow assay compared with HCs. CD4 memory T cells from axSpA patients produce more under Th17-favoring conditions (IL-1β and IL-23) than cells from PsA and RA patients or HCs.
CONCLUSION
production is increased in the synovial tissue of SpA and can be localized to CD68 macrophage-like synoviocytes, whereas circulating Th17 cells are only modestly enriched. Considering the osteoproliferative properties of , this offers new therapeutic options independent of Th17 pathways.
Topics: Humans; Arthritis, Psoriatic; Synoviocytes; Male; Adult; Female; Antigens, CD; Interleukins; Middle Aged; Antigens, Differentiation, Myelomonocytic; Axial Spondyloarthritis; Th17 Cells; Synovial Membrane; Joints; Arthritis, Rheumatoid
PubMed: 38799447
DOI: 10.3389/fimmu.2024.1355824 -
Frontiers in Immunology 2024Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and...
BACKGROUND
Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2 TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker.
METHODS
We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2 TAM subpopulations (CD68SHP2, CD68CD86, CD68 + 206, CD68 CD86SHP2, CD68 CD206SHP2) and T cells (CD8 Granzyme B ) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests.
RESULTS
In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68 SHP2 TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68SHP2 TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68SHP2 subset proportion was positively correlated with the CD68CD206 subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001).
CONCLUSIONS
The high infiltration of CD68SHP2 TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.
Topics: Humans; Tumor Microenvironment; Carcinoma, Non-Small-Cell Lung; Female; Lung Neoplasms; Antigens, CD; Male; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Antigens, Differentiation, Myelomonocytic; Middle Aged; Tumor-Associated Macrophages; Aged; Biomarkers, Tumor; Macrophages; Prognosis; Adult; CD68 Molecule
PubMed: 38799432
DOI: 10.3389/fimmu.2024.1396719