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Project description:Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.
2023-07-11 | GSE221369 | GEO
Project description:Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.
2023-07-11 | GSE235116 | GEO
Project description:Inflammasomes play important roles in the pathogenesis of tumors, but the roles of NLRP3 inflammasome in the lymphoma remain unclear. Activated NLRP3 inflammasome induces the maturation of its effector cytokine IL-18 which functions in the development of cancer. Here, we investigated the polymorphism and expression of NLRP3 inflammasome related genes and explored their function in lymphoma. We found that IL-18 (rs1946518) and NFκB94 ins/del (rs28362491) contributed to lymphoma susceptibility and allele G in IL-18 was significantly associated with the risk of lymphoma. The mRNA and plasma expression levels of IL-18 were significantly elevated in primary lymphoma patients and decreased after remission. NLRP3 inflammasome could be activated by ATP plus LPS in lymphoma cells accompanied with the increasing expression of NLRP3-related genes. NLRP3 inflammasome activation reduced the dexamethasone-induced proliferation-inhibiting effect by promoting cells into S phase. NLRP3 inflammasome activation promoted lymphoma cells proliferation and inhibited apoptosis through up-regulation of c-myc and bcl-2, and down-regulation of TP53 and bax, and then reduced the anti-tumor effect of dexamethasone. Similar with the activation of NLRP3, the effector cytokine IL-18 also had the proliferation-promoting, apoptosis-inhibiting and resistance-reducing effects on lymphoma cells via shifting the balance of c-myc/TP53 and bcl-2/bax. Moreover, neutralizing IL-18 has the opposite effects. In conclusion, NLRP3 inflammasome contributes to the susceptibility and plays a carcinogenic role through its effector cytokine IL-18 in lymphoma.
| S-EPMC5752465 | biostudies-literature
Project description:Nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) was a member of the NOD-like receptor family and played an important role in the innate immune response. Dysregulated NOD2 had been reported to contribute to tumorigenesis and progression. Here, we investigated that decreased NOD2 expressions could affect the phenotypic polarization of tumour-associated macrophages and thus lead to the poor prognosis of lung adenocarcinoma patients. We clustered the patients by the single-sample gene set enrichment analysis of tumour microenvironment and 13 prognostic differentially expressed immune-related genes (PDEIRGs) were obtained based on prognostic analyses. After multiple assessments on the 13 PDEIRGs, NOD2 was considered to be the central immune gene and had a strong effect on suppressing tumour progression. Decreased NOD2 expression could be induced by cancer cells and lead to the phenotypic polarization of macrophages from protective M1 phenotype to pro-tumorigenic M2 subtype which might be attributed to the down-regulating of NF-κB signalling pathway. This study draw attention to the role of inhibited innate immune function mediated by depletion of NOD2 in the TME. Our work also points to a potential strategy of NOD2-mediated TAM-targeted immunotherapy.
| S-EPMC8335701 | biostudies-literature
Project description:Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c- interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r-/- mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.
| S-EPMC9249769 | biostudies-literature
Project description:Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumours with OCCC-like histopathology, culminating in haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting the tumour cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signalling. We propose that ARID1A protects against inflammation-driven tumorigenesis.
| S-EPMC4308813 | biostudies-literature
Project description:By crossing LysM-Cre and TGF-? type II receptor (Tgfbr2) floxed mice we achieved specific deletion of Tgfbr2 in myeloid cells (Tgfbr2(MyeKO) mice). S.c.-injected (LLC, EL4-OVA) and implanted (MMTV-PyMT) carcinoma cells grow slower in Tgfbr2(MyeKO) mice. The number of CD45(+) cells in the tumor tissue was the same in both genotypes of mice, but upon analysis, the percentage of T cells (CD45(+)CD3(+)) in the KO mice was increased. By flow cytometry analysis, we did not detect any differences in the number and phenotype of TAMs, CD11b(+)Gr1(+), and DCs in Tgfbr2(MyeKO) compared with Tgfbr2(MyeWT) mice. ELISA and qRT-PCR data showed differences in myeloid cell functions. In Tgfbr2(MyeKO) TAMs, TNF-? secretion was increased, basal IL-6 secretion was down-regulated, TGF-? did not induce any VEGF response, and there was decreased MMP9 and increased MMP2 and iNOS expression. TGF-? did not have any effect on CD11b(+)Gr1(+) cells isolated from Tgfbr2(MyeKO) mice in the regulation of Arg, iNOS, VEGF, and CXCR4, and moreover, these cells have decreased suppressive activity relative to T cell proliferation. Also, we found that DCs from tumor tissue of Tgfbr2(MyeKO) mice have increased antigen-presented properties and an enhanced ability to stimulate antigen-specific T cell proliferation. We conclude that Tgfbr2 in myeloid cells has a negative role in the regulation of anti-tumorigenic functions of these cells, and deletion of this receptor decreases the suppressive function of CD11b(+)Gr1(+) cells and increases antigen-presenting properties of DCs and anti-tumorigenic properties of TAMs.
| S-EPMC3427612 | biostudies-literature
Project description:Anti-parasitic treatment for Chagas disease mainly relies on benznidazole, which is virtually the only drug available in the market. Besides its anti-parasitic effects, benznidazole has anti-inflammatory properties. In this work we studied the mechanisms involved in the latter, demonstrating the participation of the IL-10/STAT3/SOCS3 pathway. To achieve this goal, the anti-inflammatory properties of benznidazole were studied using an in vitro model of cardiomyocyte primary culture stimulated with LPS. LPS increased both SOCS3 expression and STAT3 phosphorylation. The addition of benznidazole increased their expression even further. Specific inhibition of STAT3 precluded this effect, suggesting a role for STAT3 in the increase of SOCS3 expression induced by benznidazole. To assess the participation of SOCS3 in the anti-inflammatory effect of benznidazole, we accomplished specific knockdown of SOCS3 with siRNA. Silencing of SOCS3 in cardiomyocytes precluded the inhibitory effects of benznidazole on TNF-α, IL-6, iNOS expression and NO release. Moreover, in the absence of SOCS3, benznidazole could neither prevent IKK phosphorylation nor IκBα degradation, supporting the notion that SOCS3 is required for the benznidazole-mediated inhibition of the NF-κB pathway. Previously, we demonstrated that IL-10 increases the expression of SOCS3 in cultured cardiomyocytes. Here, we found that benznidazole shows a trend to increased IL-10 expression. To evaluate whether benznidazole increased SOCS3 in an IL-10-dependent manner, cardiomyocytes from IL-10 knockout mice were pre-treated with benznidazole and stimulated with LPS. Benznidazole neither inhibited NO release nor avoid IKK phosphorylation or IκBα degradation, showing that IL-10 is required for benznidazole-mediated inhibition of NF-κB. Moreover, exogenous addition of IL-10 to IL-10 knockout cardiomyocytes restored the inhibitory effect of benznidazole on NO release. The results reported herein show, for the first time, that the IL-10/STAT3/SOCS3 axis is involved in the anti-inflammatory effects of benznidazole. These findings may add up to new therapeutic strategies for chronic Chagas disease given its inflammatory nature.
| S-EPMC6558013 | biostudies-literature
Project description:Scar formation occurs during the late stages of the inflammatory response but, when excessive, produces fibrosis that can lead to functional and structural damage of tissues. Here, we show that the profibrogenic agonist, transforming growth factor beta1, transcriptionally decreases expression of Exchange protein activated by cAMP 1 (Epac1) in fibroblasts/fibroblast-like cells from multiple tissues (i.e., cardiac, lung, and skin fibroblasts and hepatic stellate cells). Overexpression of Epac1 inhibits transforming growth factor beta1-induced collagen synthesis, indicating that a decrease of Epac1 expression appears to be necessary for the fibrogenic phenotype, an idea supported by evidence that Epac1 expression in cardiac fibroblasts is inhibited after myocardial infarction. Epac and protein kinase A, a second mediator of cAMP action, have opposite effects on migration but both inhibit synthesis of collagen and DNA by fibroblasts. Epac is preferentially activated by low concentrations of cAMP and stimulates migration via the small G protein Rap1 but inhibits collagen synthesis in a Rap1-independent manner. The regulation of Epac expression and activation thus appear to be critical for the integration of pro- and anti-fibrotic signals and for the regulation of fibroblast function.
| S-EPMC2359804 | biostudies-other
Project description:Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1β, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.
| S-EPMC7430972 | biostudies-literature