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Cell Feb 2018Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the...
Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE for immune evasion and that could be exploited for cancer therapy.
Topics: Animals; Cell Line, Tumor; Chemokine CCL5; Chemokines, C; Cyclooxygenase 1; Cyclooxygenase 2; Dendritic Cells; Dinoprostone; Gene Expression Regulation, Neoplastic; Humans; Killer Cells, Natural; Melanoma; Mice; Mutation; Neoplasms; Prognosis; Proto-Oncogene Proteins B-raf; Survival Analysis; Tumor Microenvironment
PubMed: 29429633
DOI: 10.1016/j.cell.2018.01.004 -
Journal of Clinical & Translational... Jun 2019The term "hyperthyroidism" indicates a condition due to an exaggerate production of thyroid hormone; the most frequent cause is Graves' disease (GD). We review cytokines... (Review)
Review
The term "hyperthyroidism" indicates a condition due to an exaggerate production of thyroid hormone; the most frequent cause is Graves' disease (GD). We review cytokines and chemokines in hyperthyroidism, with a special focus in GD. In GD, recruited Th1 lymphocytes are responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates Th1 chemokines release from thyrocytes, initiating and perpetuating the autoimmune process. Circulating levels of these chemokines are associated with the active phase of GD. Additional studies are necessary to investigate whether Th1 chemokines could be a novel therapeutic target in this disease.
PubMed: 31193493
DOI: 10.1016/j.jcte.2019.100196 -
Journal For Immunotherapy of Cancer May 2020Interleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8 T and natural killer (NK) cells. Bioactive IL-15 is produced in the body as a heterodimeric...
BACKGROUND
Interleukin-15 (IL-15) promotes growth and activation of cytotoxic CD8 T and natural killer (NK) cells. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and IL-15 receptor alpha chains (hetIL-15). Several preclinical models support the antitumor activity of hetIL-15 promoting its application in clinical trials.
METHODS
The antitumor activity of hetIL-15 produced from mammalian cells was tested in mouse tumor models (MC38 colon carcinoma and TC-1 epithelial carcinoma). The functional diversity of the immune infiltrate and the cytokine/chemokine network within the tumor was evaluated by flow cytometry, multicolor immunohistochemistry (IHC), gene expression profiling by Nanostring Technologies, and protein analysis by electrochemiluminescence and ELISA assays.
RESULTS
hetIL-15 treatment resulted in delayed primary tumor growth. Increased NK and CD8 T cell tumoral infiltration with an increased CD8/Treg ratio were found by flow cytometry and IHC in hetIL-15 treated animals. Intratumoral NK and CD8 T cells showed activation features with enhanced interferon-γ (IFN-γ) production, proliferation (Ki67), cytotoxic potential (Granzyme B) and expression of the survival factor Bcl-2. Transcriptomics and proteomics analyses revealed complex effects on the tumor microenvironment triggered by hetIL-15 therapy, including increased levels of IFN-γ and XCL1 with intratumoral accumulation of XCR1IRF8CD103 conventional type 1 dendritic cells (cDC1). Concomitantly, the production of the chemokines CXCL9 and CXCL10 by tumor-localized myeloid cells, including cDC1, was boosted by hetIL-15 in an IFN-γ-dependent manner. An increased frequency of circulating CXCR3 NK and CD8 T cells was found, suggesting their ability to migrate toward the tumors following the CXCL9 and CXCL10 chemokine gradient.
CONCLUSIONS
Our results show that hetIL-15 administration enhances T cell entry into tumors, increasing the success rate of immunotherapy interventions. Our study further supports the incorporation of hetIL-15 in tumor immunotherapy approaches to promote the development of antitumor responses by favoring effector over regulatory cells and by promoting lymphocyte and DC localization into tumors through the modification of the tumor chemokine and cytokine milieu.
Topics: Animals; CD8-Positive T-Lymphocytes; Chemokine CXCL10; Chemokine CXCL9; Chemokines, C; Colonic Neoplasms; Cytokines; Dendritic Cells; Immunotherapy; Interferon-gamma; Interleukin-15; Interleukin-15 Receptor alpha Subunit; Killer Cells, Natural; Mice; Mice, Inbred C57BL; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Tumor Microenvironment
PubMed: 32461349
DOI: 10.1136/jitc-2020-000599 -
American Journal of Respiratory Cell... Nov 2015Macrophages are dynamic cells that mature under the influence of signals from the local microenvironment into either classically (M1) or alternatively (M2) activated...
Macrophages are dynamic cells that mature under the influence of signals from the local microenvironment into either classically (M1) or alternatively (M2) activated macrophages with specific functional and phenotypic properties. Although the phenotypic identification of M1 and M2 macrophages is well established in mice, this is less clear for human macrophages. In addition, the persistence and reversibility of polarized human phenotypes is not well established. Human peripheral blood monocytes were differentiated into uncommitted macrophages (M0) and then polarized to M1 and M2 phenotypes using LPS/IFN-γ and IL-4/IL-13, respectively. M1 and M2 were identified as CD64(+)CD80(+) and CD11b(+)CD209(+), respectively, by flow cytometry. Polarized M1 cells secreted IP-10, IFN-γ, IL-8, TNF-α, IL-1β, and RANTES, whereas M2 cells secreted IL-13, CCL17, and CCL18. Functionally, M2 cells were highly endocytic. In cytokine-deficient medium, the polarized macrophages reverted back to the M0 state within 12 days. If previously polarized macrophages were given the alternative polarizing stimulus after 6 days of resting in cytokine-deficient medium, a switch in polarization was seen (i.e., M1 macrophages switched to M2 and expressed CD11b(+)CD209(+) and vice versa). In summary, we report phenotypic identification of human M1 and M2 macrophages, their functional characteristics, and their ability to be reprogrammed given the appropriate stimuli.
Topics: Cell Differentiation; Chemokine CCL17; Chemokine CCL5; Chemokine CXCL10; Chemokines, CC; Endocytosis; Gene Expression; Humans; Immunophenotyping; Interferon-gamma; Interleukin-13; Interleukin-1beta; Interleukin-4; Interleukin-8; Lipopolysaccharides; Macrophage Activation; Macrophages; Monocytes; Primary Cell Culture; Tumor Necrosis Factor-alpha
PubMed: 25870903
DOI: 10.1165/rcmb.2015-0012OC -
La Clinica Terapeutica 2019High levels of chemokine (C-X-C motif) receptor (CXCR)3 and monokine induced by interferon (IFN)-γ (MIG) expression were revealed in the intestinal mucosa of mice with... (Review)
Review
High levels of chemokine (C-X-C motif) receptor (CXCR)3 and monokine induced by interferon (IFN)-γ (MIG) expression were revealed in the intestinal mucosa of mice with experimental colitis, and in lymphocytes, macrophages and epithelial cells of patients with Crohn's disease (CD). CXCR3 and its chemokines expression were induced by IFN-γ in epithelial intestinal cells. These chemokines are involved in the recruitment of granulocytes and mononuclear cells, therefore in the maintenance of inflammation in CD. Serum MIG levels reflect CD disease activity, and it could be a marker for the responsiveness of patients to treatments. Efforts have been made to block MIG or CXCR3 in CD as a potential therapy of CD.
Topics: Animals; Biomarkers; Chemokine CXCL9; Chemokines; Crohn Disease; Epithelial Cells; Humans; Intestinal Mucosa; Leukocytes; Lymphocytes; Mice; Receptors, CXCR3
PubMed: 31173051
DOI: 10.7417/CT.2019.2134 -
La Clinica Terapeutica 2017Hypersensitivity pneumonitis (HP) is categorized as a Type-1 helper (Th1) disease. The resulting granuloma formation is dependent on T cells and the Th1 cytokine... (Review)
Review
Hypersensitivity pneumonitis (HP) is categorized as a Type-1 helper (Th1) disease. The resulting granuloma formation is dependent on T cells and the Th1 cytokine interferon (IFN)-γ. In experimental setting, the production of IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ (MIG), IFN-inducible T-cell-alpha chemoattractant (I-TAC), has been shown (in mice exposed to the particulate antigens that cause HP) during the development of HP. The production of these chemokines was associated with an influx of chemokine (C-X-C motif) receptor (CXCR)3 CXCR3(+)/CD4(+) T cells into lungs. This suggests that IFN-γ mediates the recruitment of CXCR3(+)/CD4(+) T cells into the lung via the production of IP-10, MIG, and I-TAC, resulting in granuloma formation. In humans it has been shown that lymphocytes infiltrating lung biopsies are CD8 T cells for CXCR3. Furthermore, the T cells accumulating in the bronchoalveolar lavage (BAL) of HP were CXCR3(+)/IFN-γ(+) type 1 CD8(+) T cells (Tc1) exhibiting a strong in vitro migratory capability in response to IP-10. Alveolar macrophages express and secrete, in response to IFN-γ, high levels of IP-10, capable of inducing chemotaxis of the CXCR3(+) T-cell line. High levels of CXCR3 ligands were shown in the fluid of the BAL in HP patients. These data confirm that IFN-γ mediates the recruitment of lymphocytes into the lung via production of IP-10, resulting in Tc1-cell alveolitis and granuloma formation. It has been suggested that differences in the expression of CXC chemokines and Th1 cytokines may contribute to different immunopathogenesis, clinical course and responsiveness to treatment of HP.
Topics: Alveolitis, Extrinsic Allergic; Animals; CD8-Positive T-Lymphocytes; Chemokine CXCL10; Chemokine CXCL9; Humans; Interferon-gamma; Lung; Mice; Receptors, CXCR3
PubMed: 28383627
DOI: 10.7417/CT.2017.1996 -
JCI Insight Dec 2019NK cells contribute to protective antitumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we...
NK cells contribute to protective antitumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis identified major differences in the transcriptional programs of tumor-infiltrating compared with circulating NK cells. Tumor-infiltrating NK cells represented 7 clusters with distinct gene expression programs indicative of significant functional specialization, including cytotoxicity and chemokine synthesis programs. In particular, NK cells from 3 clusters expressed high levels of XCL1 and XCL2, which encode 2 chemokines known to recruit XCR1+ cross-presenting DCs into tumors. In contrast, NK cells from 2 other clusters showed a higher level of expression of cytotoxicity genes. These data reveal key features of NK cells in human tumors and identify NK cell populations with specialized gene expression programs.
Topics: Cell Line, Tumor; Chemokines; Chemokines, C; Cross-Priming; Gene Expression Regulation, Neoplastic; Humans; Immunity, Innate; Killer Cells, Natural; Lymphocytes, Tumor-Infiltrating; Melanoma; Neoplasm Metastasis
PubMed: 31801909
DOI: 10.1172/jci.insight.133103 -
La Clinica Terapeutica 2017The underlying mechanism of allergic rhinitis involves IgE antibodies attaching to the allergen and causing the release of inflammatory chemicals such as histamine from... (Review)
Review
The underlying mechanism of allergic rhinitis involves IgE antibodies attaching to the allergen and causing the release of inflammatory chemicals such as histamine from mast cells. Cytokines are very important in this process. Many data suggest a systemic shift to more intensely type 1-dominated immune responses in non-allergic individuals and, conversely, to more type 2-dominated responses in allergic individuals upon natural re-exposure to grass pollen. However other studies have found that chemokine (C-X-C motif) ligand (CXCL)10/ interferon (IFN)-γ-induced protein 10 (IP-10) and CXCL9/monokine induced by IFN-γ (MIG) concentrations are elevated in nasal lavages from allergic patients suggesting that these chemokines may play a role in chronic allergic inflammation. Several studies have also evaluated the effect of different immune-modulating drugs in allergic rhinitis showing local and peripheral increase of IFN-γ and IP-10, associated with a reduction of symptoms. Further studies are needed to clarify the role of T helper (Th)1 chemokines in the pathogenesis of allergic rhinitis, and to evaluate their role as biomarkers of disease and of response to treatments.
Topics: Allergens; Chemokine CXCL10; Chemokine CXCL9; Cytokines; Humans; Interferon-gamma; Receptors, CXCR3; Rhinitis, Allergic
PubMed: 28240764
DOI: 10.7417/CT.2017.1983 -
La Clinica Terapeutica 2017Hepatocellular carcinoma (HCC) results from several factors like viral hepatitis infection [hepatitis B, or C (25%)] or occupational exposure. T-helper (Th)1... (Review)
Review
Hepatocellular carcinoma (HCC) results from several factors like viral hepatitis infection [hepatitis B, or C (25%)] or occupational exposure. T-helper (Th)1 inflammatory cells, characterized by interferon (IFN)-γ and interleukin (IL)-2 secretion, predominate in the liver during chronic HCV infection, and chemokines attracting these cells are particularly important in disease progression. Among C-X-C chemokines, the non-ELR group [as IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ (MIG) and IFN-inducible T-cell-alpha chemoattractant (I-TAC)], attracts Th1-cells interacting with chemokine C-X-C receptor (CXCR3). IP-10 has uniquely been shown to have prognostic utility as a marker of treatment outcome. IFN- γ-induced chemokines, as MIG and IP-10, may promote lymphocyte recruitment to HCC playing important roles in cancer immunology. The production of CXC chemokines by HCC cell lines has been shown. It has been identified immune-gene signature that predicts patient survival including the chemokine gene IP-10. Inflammatory cytokines (tumour necrosis factor-α, IFN-γ) and Toll-like receptor 3 ligands stimulate intratumoral production of these chemokines which drive T and Natural Killer cells tumor infiltration, leading to enhanced cancer cell death. Furthermore selective recruitment of CXCR3(+) B-cells that bridges proinflammatory IL-17 response and protumorigenic macrophage polarization in HCC has been shown, suggesting that blocking CXCR3(+) B-cell migration or function may help defeat HCC. It has been also shown that the overexpression of IP-10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway in HCC; IP-10 neutralizing antibody could be a potential adjuvant therapy to sensitize HCC-cisplatin treatment.
Topics: Carcinoma, Hepatocellular; Chemokine CXCL10; Endoplasmic Reticulum Chaperone BiP; Humans; Interferon-gamma; Interleukin-17; Liver Neoplasms; Receptors, CXCR3; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha
PubMed: 28240761
DOI: 10.7417/CT.2017.1980 -
La Clinica Terapeutica 2019Chemokine (C-X-C motif) ligand (CXCL)9/monokine induced by interferon (IFN)-γ (MIG) and its receptor, chemokine (C-X-C motif) receptor (CXCR)3, are involved in the... (Review)
Review
Chemokine (C-X-C motif) ligand (CXCL)9/monokine induced by interferon (IFN)-γ (MIG) and its receptor, chemokine (C-X-C motif) receptor (CXCR)3, are involved in the pathogenesis of Graves' ophthalmopathy (GO). In tissues, recruited Type 1 helper (Th1) lymphocytes could cause an increased production of IFN-γ and tumor necrosis factor (TNF)-α, which in turn stimulate MIG secretion from these cells; all this creates an amplification feedback loop, and perpetuates the autoimmune process. In particular, MIG is secreted by fibroblasts and preadipocytes under the influence of IFN-γ. The IFN-γ induced MIG secretion in vitro, in GO fibroblasts and preadipocytes can be modulate by peroxisome proliferator-activated receptors (PPAR)-γ and PPAR-α activators. High levels of MIG in peripheral liquids could be considered as a marker of an especially Th1 orientated immune response. The presence of circulating MIG is associated with the active phase of GO. An increased concentrations of MIG in patients with GO reflect, at least in part, the orbital inflammation activity. Since MIG concentrations are significantly reduced during corticosteroids and/or radiotherapy treatments, with respect to control group and basal values of patients with GO, MIG has been proposed as a marker in the therapy choice for patients with GO. More studies are needed to investigate interactions between chemokines and cytokines in the GO pathogenesis and to evaluate whether MIG is a novel therapeutic target in these autoimmune disorders.
Topics: Chemokine CXCL10; Chemokine CXCL9; Chemokines; Graves Ophthalmopathy; Humans; Receptors, CXCR3; Th1 Cells; Tumor Necrosis Factor-alpha
PubMed: 31612195
DOI: 10.7417/CT.2019.2162