Topical TLR7 agonist and radiotherapy in patients with metastatic breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE282443 | GEO | 2025/04/16
REPOSITORIES: GEO
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Project description:Leaf-to-leaf, systemic immune signaling known as systemic acquired resistance (SAR) is poorly understood in monocotyledonous plants. Here, we characterize systemic immunity in barley (Hordeum vulgare) triggered after primary leaf infection with either Pseudomonas syringae pathovar japonica (Psj) or Xanthomonas translucens pathovar cerealis (Xtc). Both pathogens induced resistance in systemic, uninfected leaves against a subsequent challenge infection with Xtc. In contrast to SAR in Arabidopsis thaliana, systemic immunity in barley was not associated with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 or the local or systemic accumulation of salicylic acid (SA). Instead, we documented a moderate local but not systemic induction of abscisic acid (ABA) after infection of leaves with Psj. In contrast to SA or its functional analog benzothiadiazole, local applications of the jasmonic acid methyl ester or ABA triggered systemic immunity to Xtc. RNA-seq analysis of local and systemic transcript accumulation revealed unique gene expression changes in response to both Psj and Xtc and a clear separation of local from systemic responses. The systemic response appeared relatively modest and quantitative RT-PCR associated systemic immunity with the local and systemic induction of two WRKY and two ETHYLENE RESPONSIVE FACTOR-like transcription factors. Systemic immunity against Xtc was further associated with transcriptional changes after a secondary/systemic Xtc challenge infection; these changes were dependent on the primary treatment. Taken together, bacteria-induced systemic immunity in barley may be mediated in part by WRKY and ERF-like transcription factors possibly facilitating transcriptional reprogramming to potentiate immunity.
2014-11-24 | E-MTAB-3056 | biostudies-arrayexpress
Project description:Leaf-to-leaf, systemic immune signaling known as systemic acquired resistance (SAR) is poorly understood in monocotyledonous plants. Here, we characterize systemic immunity in barley (Hordeum vulgare) triggered after primary leaf infection with either Pseudomonas syringae pathovar japonica (Psj) or Xanthomonas translucens pathovar cerealis (Xtc). Both pathogens induced resistance in systemic, uninfected leaves against a subsequent challenge infection with Xtc. In contrast to SAR in Arabidopsis thaliana, systemic immunity in barley was not associated with NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 or the local or systemic accumulation of salicylic acid (SA). Instead, we documented a moderate local but not systemic induction of abscisic acid (ABA) after infection of leaves with Psj. In contrast to SA or its functional analog benzothiadiazole, local applications of the jasmonic acid methyl ester or ABA triggered systemic immunity to Xtc. RNA-seq analysis of local and systemic transcript accumulation revealed unique gene expression changes in response to both Psj and Xtc and a clear separation of local from systemic responses. The systemic response appeared relatively modest and quantitative RT-PCR associated systemic immunity with the local and systemic induction of two WRKY and two ETHYLENE RESPONSIVE FACTOR-like transcription factors. Systemic immunity against Xtc was further associated with transcriptional changes after a secondary/systemic Xtc challenge infection; these changes were dependent on the primary treatment. Taken together, bacteria-induced systemic immunity in barley may be mediated in part by WRKY and ERF-like transcription factors possibly facilitating transcriptional reprogramming to potentiate immunity.
2014-11-24 | E-MTAB-3063 | biostudies-arrayexpress
Project description:<p><strong>OBJECTIVES:</strong> High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.</p><p><strong>MATERIALS AND METHODS:</strong> Systemic IDO1 activity was calculated by Kyn:Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. Dynamic change of IDO1 activity was followed in 24 patients by measuring Kyn:Trp ratio before, during and after RT administration.</p><p><strong>RESULTS:</strong> In 24 patients with dynamic tracking of plasma IDO1 activity, there was no significant alterations observed among the 3 time points (Friedman test, p=0.13). The changing pattern of Kyn:Trp ratio was divided into 4 groups: decreased consistently during RT, first increased then decreased, increased consistently, first decreased then increased. Patients whose Kyn:Trp ratio kept decreasing or first increased then decreased were defined as good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p=0.04; p=0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than bad-change group (p=0.01, HR=0.22). In 113 stage III NSCLC patients with pre-radiation Kyn:Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p=0.079).</p><p><strong>CONCLUSION: </strong>Favorable change of IDO1 activity during RT was associated with superior OS, PFS and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.</p>
2022-08-05 | MTBLS5267 | MetaboLights
Project description:A systemic view of coordinated root responses to NO3- heterogeneous environment in Arabidopsis
2015-05-20 | E-GEOD-22966 | ExpressionAtlas
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that Myd88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which Myd88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, aged-associated B cells (ABCs) were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of the ABC subset in pSS.
2022-09-01 | GSE212467 | GEO
Project description:Radiotherapy (RT) destroys tumor cells, which may lead to release of antigens and immune-activating signals. In this way, RT may act as an in situ vaccine and kick-start a T-cell response against the tumor. Immunotherapy enhances tumor-specific T-cell responses. Combination of radiotherapy and immunotherapy (radio-immunotherapy (RIT)) can therefore be expected to synergize in inducing and sustaining systemic anti-tumor T-cell responses. However, in the clinic, systemic combined responses between radiotherapy and immunotherapy are rarely observed, as the effect of RIT combinations on ‘abscopal’ tumors outside the radiotherapy field are not (yet) greater than the effect of immunotherapy alone. In order to define potential bottlenecks in the tumor micro-environment that impede CD8 T cell activity, we harvested irradiated and non-irradiated tumors from the same mice that were treated with RIT (10 Gy RT, anti-CD137 and anti-PD1). From these tumors, effector (CD43+) CD8 T cells, ‘other’ hematopoietic (CD45+) cells and tumor/stromal (CD45-) were sorted and RNA sequencing was performed to identify differences between these cell populations in the irradiated and non-irradiated tumors that could explain the lack of T cell activity in the non-irradiated tumor.
2019-02-12 | E-MTAB-6914 | biostudies-arrayexpress
Project description:The primary objective is to compare multiplex immune response signatures following two (primary and a boost) vaccinations with the GSK AS03 adjuvanted H5N1 influenza vaccine or the non-adjuvanted form of the H5N1 influenza vaccine at the 3.75 mcg dose and given 21 days apart and identify differences in very early innate immune responses. These immune signatures will also be correlated with the clinical observations especially safety related local and systemic events.
2024-11-05 | GSE112293 | GEO
Project description:By their selective infection or replication into tumors, oncolytic viruses trigger profound modifications of tumor immune microenvironment with a massive infiltration and activation of T cells. This tumor warming up can be further amplified by the local delivery of powerful immunomodulatory molecules encoded into virus’ genome. Those properties are particularly of interest for tumor poorly infiltrated or infiltrated with anergic T cells to reverse patient’s unresponsiveness to immune checkpoint inhibitors (ICI). TG6050 is a new oncolytic vaccinia virus encoding single-chain human Interleukin-12 (hIL-12) and full length anti-cytotoxic T-lymphocyte-associated antigen-4 (@CTLA-4) monoclonal antibody. Replication, oncolysis, selectivity, transgenes expression and functionality of TG6050 were characterized in vitro. Virus and IL-12 pharmacokinetics, antitumoral activities (alone or combined with ICI), and mechanism of action (MOA) were investigated in “hot” (highly infiltrated) and “cold” (poorly infiltrated) syngeneic murine tumor models. MOA was deciphered by monitoring both systemic and tumor immune responses, and tumor transcriptome analyses. Finally, TG6050 safety after repeated intravenous administrations was evaluated in cynomolgus monkeys and special attention was paid to the level of circulating IL-12 potentially associated with toxic effects. In vitro or in vivo replication of TG6050 in tumor cells allows local expression of functional IL-12 and @CTLA-4. The expression of transgenes, together with the virus replication, translated into an antitumoral activity in both “cold and “hot” tumor murine models that was further amplified by combination with ICI. Analysis of tumor microenvironment (TME) after TG6050 treatment showed an increase of interferon gamma, CD8+ T cells, M1/M2 macrophages ratio and a drastic decrease of regulatory T cells. Those local modifications were observed together with an enhanced systemic and specific antitumor adaptive immune response. In toxicology studies, the virus did not produce any observable adverse effects in cynomolgus monkeys. Conclusions: TG6050 allows the delivery of functional IL-12 and @CTLA-4 into tumor resulting in an excellent antitumor activity along with a shift towards an inflamed TME, and a boost of the systemic antitumor T-cells. Toxicological studies in macaques demonstrated the safety of TG6050. Together these results paved the way for clinical evaluation of TG6050 in metastatic non-small cell lung cancer (NCT05788926).
2024-07-30 | GSE259380 | GEO
Project description:By their selective infection or replication into tumors, oncolytic viruses trigger profound modifications of tumor immune microenvironment with a massive infiltration and activation of T cells. This tumor warming up can be further amplified by the local delivery of powerful immunomodulatory molecules encoded into virus’ genome. Those properties are particularly of interest for tumor poorly infiltrated or infiltrated with anergic T cells to reverse patient’s unresponsiveness to immune checkpoint inhibitors (ICI). TG6050 is a new oncolytic vaccinia virus encoding single-chain human Interleukin-12 (hIL-12) and full length anti-cytotoxic T-lymphocyte-associated antigen-4 (@CTLA-4) monoclonal antibody. Replication, oncolysis, selectivity, transgenes expression and functionality of TG6050 were characterized in vitro. Virus and IL-12 pharmacokinetics, antitumoral activities (alone or combined with ICI), and mechanism of action (MOA) were investigated in “hot” (highly infiltrated) and “cold” (poorly infiltrated) syngeneic murine tumor models. MOA was deciphered by monitoring both systemic and tumor immune responses, and tumor transcriptome analyses. Finally, TG6050 safety after repeated intravenous administrations was evaluated in cynomolgus monkeys and special attention was paid to the level of circulating IL-12 potentially associated with toxic effects. In vitro or in vivo replication of TG6050 in tumor cells allows local expression of functional IL-12 and @CTLA-4. The expression of transgenes, together with the virus replication, translated into an antitumoral activity in both “cold and “hot” tumor murine models that was further amplified by combination with ICI. Analysis of tumor microenvironment (TME) after TG6050 treatment showed an increase of interferon gamma, CD8+ T cells, M1/M2 macrophages ratio and a drastic decrease of regulatory T cells. Those local modifications were observed together with an enhanced systemic and specific antitumor adaptive immune response. In toxicology studies, the virus did not produce any observable adverse effects in cynomolgus monkeys. Conclusions: TG6050 allows the delivery of functional IL-12 and @CTLA-4 into tumor resulting in an excellent antitumor activity along with a shift towards an inflamed TME, and a boost of the systemic antitumor T-cells. Toxicological studies in macaques demonstrated the safety of TG6050. Together these results paved the way for clinical evaluation of TG6050 in metastatic non-small cell lung cancer (NCT05788926).
2024-07-30 | GSE259379 | GEO
Project description:Cyclophosphamide (CPA) treatment on a six-day repeating metronomic schedule induces a dramatic, innate immune cell-dependent regression of implanted gliomas. However, little is known about the underlying mechanisms of innate immune cell mobilization and recruitment, or about the role of DNA damage and cell stress response pathways in eliciting the anti-tumor immune responses linked to tumor regression. To address these questions, we compared untreated and 6-day metronomic cyclophosphamide-treated human U251 glioblastoma xenografts by human microarray analysis to identify responsive tumor cell-specific factors. Human glioma U251 tumors were implanted sc in scid immunodeficient mice then treated with cyclophosphamide at 140 mg/kg every 6 days. Tumors were collected 6 days after the second cyclophosphamide treatment and also 6 days after the third cyclophosphamide treatment. Tumor RNA was then analyzed on two color Agilent human expression microarrays comparing cyclophosphamide-treated RNA to untreated control tumor RNA.
2015-05-04 | E-GEOD-60867 | biostudies-arrayexpress