The immunosuppressive phenotype of tumor-infiltrating neutrophils is associated with obesity in kidney cancer patients.
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ABSTRACT:
SUBMITTER: Margaroli C
PROVIDER: S-EPMC7153842 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor-associated macrophages (TAMs) support tumor progression within the tumor microenvironment (TME). Many questions remain as to the origin, development, and function of TAMs within the prostate TME. Evaluation of TAMs in prostate cancer (PCa) patients identified the immunosuppressive TAM marker CD163 in adjacent normal epithelium as an independent predictor of metastases or PCa death. Flow cytometry analyses identified prostate TAMs as frequently expressing both proinflammatory M1 (CCR7+) and immunosuppressive M2 (CD163+) markers. In vitro, we demonstrate PCa cells similarly subvert human M1 macrophages toward a mixed M1/M2 macrophage phenotype favoring tumor growth. Further the cytokine milieu-induced transition between immunosuppressive M2 to proinflammatory M1 (M2→M1) macrophages is abrogated by the presence of PCa cells. RNA sequencing suggests alterations in chemokine expression in prostate TAMs due to the presence of PCa cells. Together, our results suggest that prostate TAMs originate from inflammatory infiltrating macrophages, which are then reprogrammed mainly by PCa cells, but also the cytokine milieu. A better understanding of this subversion of macrophages within the prostate may lead to novel treatment strategies.
| S-EPMC8786699 | biostudies-literature
Project description:Tumor-infiltrating neutrophils (TIN) carry out quite significant but opposite functions in different cancers, and their function in biliary cancer has not been fully characterized. To investigate the prognostic significance of TIN in biliary cancer, a training set (n = 118) and a validation set (n = 127) were involved in this study. TIN were evaluated by immunohistochemical staining of CD66b, and then defined as low (neutrophils <18/high-power field [HPF]) vs high (neutrophils ≥18/HPF). Kaplan-Meier curve, Cox proportional hazards models and receiver operating characteristic curve were used to assess the prognostic significance. TIN was identified as an independent prognostic factor for overall survival in the training set (HR: 4.720; 95% CI: 2.623-8.493; P < .001) which was confirmed in the validation set (HR: 4.993; 95% CI: 2.626-9.492; P < .001). Notably, among patients with stage III and IV disease, those with low TIN could benefit from adjuvant chemotherapy, with a reduced risk of compromised survival compared with those with high TIN (HR: 0.294; 95% CI: 0.099-0.873; P = .047 in the training set; and HR: 0.100; 95% CI: 0.022-0.462; P = .006 in the validation set). In addition, TIN were negatively related to biological pathways as regulation of activated T-cell proliferation and lymphocyte-mediated immunity, and showed a negative correlation with CD8 + T cells (r = -.324, P < .001). Taken together, our results implicate TIN as an independent marker of prognosis and indicator of patients who would benefit from adjuvant chemotherapy in biliary cancer.
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Project description:BackgroundMUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored.MethodsThe correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro.ResultsThe serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b+, CD66b+, and ICAM-1+ neutrophils were significantly increased, while the proportion of CXCR4+ neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1β, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro.ConclusionMUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.
| S-EPMC10466733 | biostudies-literature
Project description:Meningiomas WHO grade I and II are common intracranial tumors in adults that normally display a benign outcome, but are characterized by a great clinical heterogeneity and frequent recurrence of the disease. Although the presence of an immune cell infiltrate has been documented in these tumors, a clear phenotypical and functional characterization of the immune web is missing. Here, we performed an extensive immunophenotyping of peripheral blood and fresh tumor tissue at surgery by multiparametric flow cytometry in 34 meningioma patients, along with immunosuppressive activity of sorted cells of myeloid origin. Four subsets of myeloid cells, phenotypically corresponding to myeloid-derived suppressor cells (MDSCs) are detectable in the blood and in the tumor tissue of patients and three of them are significantly expanded in the blood of patients, but show no evidence of suppressive activity. At the tumor site, a large leukocyte infiltrate is present, predominantly constituted by CD33+ myeloid cells, largely composed of macrophages endowed with suppressive activity and significantly expanded in grade II meningioma patients as compared to grade I.
| S-EPMC5993508 | biostudies-literature
Project description:Growing evidence shows tumor-infiltrating neutrophils (TINs) involvement in tumorigenesis. The objective of this study is to assess the prognostic effect of TINs and its impact on adjuvant chemotherapy benefits in muscle invasive bladder cancer (MIBC). A total of 142 MIBC patients from Zhongshan Hospital, 119 MIBC patients from FUSCC, and 405 MIBC patients from TCGA cohort were enrolled in the study. TINs were evaluated by immunohistochemical staining of CD66b or the CIBERSORT method. Patients with high TINs had a significantly poorer overall survival (p = 0.001, p < 0.001, and p = 0.002, respectively) in the three sets. In the multivariate analysis, the presence of high TINs (HR = 2.122, p = 0.007; HR = 3.807, p < 0.001; HR = 2.104, p = 0.001; respectively) was identified as an independent prognostic factor for overall survival in the three sets. More importantly, Low TINs patients had significantly longer overall survival in patients without ACT in the three sets. Gene set enrichment analysis showed that lymphocyte activation (p < 0.001) and T cell activation (p = 0.008) were significantly enriched in the low TINs group. In addition, TINs were negatively correlated with CD8+ T cells, suggesting that the status of high-TINs was linked to the status of immunosuppression in MIBC. TINs could be used as independent prognostic factor. Low TINs identified a subgroup of MIBC patients who appeared to benefit from adjuvant chemotherapy. Incorporation of TINs into TNM system could further stratify patients with different prognosis.
| S-EPMC5414863 | biostudies-literature
Project description:BACKGROUND:Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. METHODS:By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b+ tumor-associated-neutrophils (TAN) and CD3+ T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. RESULTS:Basal type BC contained a significantly higher density of CD66b+ TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T celsl and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. CONCLUSIONS:TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.
| S-EPMC7072276 | biostudies-literature
Project description:BackgroundProstate cancer is characterized by T-cell exclusion, which is consistent with their poor responses to immunotherapy. In addition, T-cells restricted to the adjacent stroma and benign areas are characterized by anergic and immunosuppressive phenotypes. In order for immunotherapies to produce robust anti-tumor responses in prostate cancer, this exclusion barrier and immunosuppressive microenvironment must first be overcome. We have previously identified mesenchymal stem cells (MSCs) in primary and metastatic human prostate cancer tissue.MethodsAn Opal Multiplex immunofluorescence assay based on CD73, CD90, and CD105 staining was used to identify triple-labeled MSCs in human prostate cancer tissue. T-cell suppression assays and flow cytometry were used to demonstrate the immunosuppressive potential of primary MSCs expanded from human bone marrow and prostate cancer tissue from independent donors.ResultsEndogenous MSCs were confirmed to be present at sites of human prostate cancer. These prostate cancer-infiltrating MSCs suppress T-cell proliferation in a dose-dependent manner similar to their bone marrow-derived counterparts. Also similar to bone marrow-derived MSCs, prostate cancer-infiltrating MSCs upregulate expression of PD-L1 and PD-L2 on their cell surface in the presence of IFNγ and TNFα.ConclusionProstate cancer-infiltrating MSCs suppress T-cell proliferation similar to canonical bone marrow-derived MSCs, which have well-documented immunosuppressive properties with numerous effects on both innate and adaptive immune system function. Thus, we hypothesize that selective depletion of MSCs infiltrating sites of prostate cancer should restore immunologic recognition and elimination of malignant cells via broad re-activation of cytotoxic pro-inflammatory pathways.
| S-EPMC6549513 | biostudies-literature
Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-24 | GSE213861 | GEO
Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-19 | GSE205371 | GEO
Project description:In patients with pancreatic ductal adenocarcinoma (PDAC), the tumor microenvironment consists of cellular and stromal components that influence prognosis. Hence, tumor-infiltrating lymphocytes (TILs) may predict prognosis more precisely than conventional staging systems. Studies on the impact of TILs are heterogeneous and further research is needed. Therefore, this study aims to point out the importance of peritumoral TILs, tumor-infiltrating neutrophils (TINs), and immune subtype classification in PDAC. Material from 57 patients was analyzed with immunohistochemistry performed for CD3, CD8, CD20, CD66b, ?-sma, and collagen. Hot spots with peritumoral TILs and TINs were quantified according to the QTiS algorithm and the distance of TILs hot spots to the tumor front was measured. Results were correlated with overall (OS) and progression-free survival (PFS). High densities of peritumoral hot spots with CD3?, CD8?, and CD20? TILs correlated significantly with improved OS and PFS. Combined immune cell subtypes predicted improved OS and PFS. High infiltration of CD3? TILs predicted progression after 12 months. The location of TILs' hot spots and their distance to the tumor front did not correlate with patient survival. Peritumoral TILs and the composition of the stroma predict OS and PFS in PDAC.
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