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IL-9 promoted pancreatic cancer cells proliferation and metastasis. (a) Proliferation of PANC-1 and AsPC-1 cells was increased with the elevation of IL-9 concentration tested by CCK8 methods. (b)-(c) The invasion and migration rate of PANC-1 and AsPC-1 cells was increased after IL-9 treatment using Transwell assay. Data was expressed as mean ± SD. p∗<0.05. p∗∗<0.01.
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Background . Both IL-9 and miR-200a are involved in the pathogenesis of cancers; however, the role of IL-9 in pancreatic cancer and the possible underlying mechanisms remain unknown. The aim of this study was to investigate the effect of IL-9 on pancreatic cancer cells and its interaction with miR-200a. Methods . Pancreatic cancer cells (PANC-1 and...
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Citations
... Furthermore, these findings are supported by increased IL-9 levels in colorectal cancer (CRC) tissue samples when compared with healthy adjacent tissues from the same individual (Gerlach et al., 2022;Tian et al., 2018). According to another study examining the effects of IL-9 in pancreatic cancer cells, IL-9 was demonstrated to directly promote proliferation by regulating the miR-200a/bcatenin axis (Hu et al., 2017). ...
Interleukin 9 (IL-9) is a cytokine with potent proinflammatory properties that plays a central role in pathologies such as allergic asthma, immunity to parasitic infection, and autoimmunity. More recently, IL-9 has garnered considerable attention in tumor immunity. Historically, IL-9 has been associated with a protumor function in hematological malignancies and an antitumor function in solid malignancies. However, recent discoveries of the dynamic role of IL-9 in cancer progression suggest that IL-9 can act as both a pro- or antitumor factor in various hematological and solid malignancies. This review summarizes IL-9-dependent control of tumor growth, regulation, and therapeutic applicability of IL-9 blockade and IL-9-producing cells in cancer.
... During the last decade, multiple studies have revealed the contribution of IL-9 to tumor immunity. IL-9 has opposing effects on IL-9R-positive tumor cells: from cytostatic and cytotoxic effects [16] to promoting tumor cell growth and migration [17,18]. IL-9 can also potently promote an anti-tumor immune response in different murine models [19]. ...
PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy.
... IL9 is a pleiotropic molecule, known as a multifaceted regulator of immune responses in different cell types. In the past, preclinical results from cell experiments described IL9 as a tumor-supportive cytokine promoting proliferation and metastasis in pancreatic cancer cells (20). And a targeted blockade of IL9 led to a restrained tumor growth in a murine model of pancreatic cancer (21). ...
Background
The peritumoral stroma is a hallmark of pancreatic ductal adenocarcinoma (PDA) with implications for disease development, progression and therapy resistance. We systematically investigated immune features of the stroma in PDA patients to identify markers of clinical importance and potential therapeutic targets.
Methods
Tissue and blood samples of 51 PDA patients with clinical and follow-up information were included. Laser Capture Microdissection allowed us to analyze the stromal compartment in particular. Systematic immunohistochemistry, followed by software-based image analysis were conducted. Also, multiplex cytokine analyses (including 50 immune-related molecules) were performed. Functional analyses were performed using patient-derived 3D bioprints. Clinical information was used for survival analyses. Intercompartmental IL9 and IL18 gradients were assessed in matched samples of tumor epithelium, stroma, and serum of patients. Serum levels were compared to an age-matched healthy control group.
Results
Stromal IL9 and IL18 are significantly associated with patient survival. While IL9 is a prognostic favorable marker (p=0.041), IL18 associates with poor patient outcomes (p=0.030). IL9 correlates with an anti-tumoral cytokine network which connects regulation of T helper (Th) 9, Th1 and Th17 cells (all: p<0.05 and r>0.5). IL18 correlates with a Th1-type cytokine phenotype and stromal CXCL12 expression (all: p<0.05 and r>0.5). Further, IL18 associates with a higher level of exhausted T cells. Inhibition of IL18 results in diminished Th1- and Th2-type cytokines. Patients with high stromal IL9 expression have a tumor-to-stroma IL9 gradient directed towards the stroma (p=0.019). Low IL18 expression associates with a tumor-to-stroma IL18 gradient away from the stroma (p=0.007). PDA patients showed higher serum levels of IL9 than healthy controls while serum IL18 levels were significantly lower than in healthy individuals. The stromal immune cell composition is distinct from the tumor epithelium. Stromal density of FoxP3⁺ regulatory T cells showed a tendency towards improved patient survival (p=0.071).
Conclusion
An unexpected high expression of the cytokines IL9 and IL18 at different ends is of significance in the stroma of PDA and relates to opposing patient outcomes. Sub-compartmental cytokine analyses highlight the importance of a differentiated gradient assessment. The findings suggest stromal IL9 and/or IL18 as markers for patient stratification and as potential therapeutic targets. Future steps include investigating e. g. the role of local microbiota as both cytokines are also regulated by microbial compositions.
... 44 Differently, IL-9 promotes the proliferation of pancreatic tumour cells as a result of miR-200a dysregulation. 45 Importantly, mRNA detection assays revealed the low level of IL-2 expression in breast tumour cells could be related to the failure of T cells activation and consequently scaping the tumour from the immune system. 46,47 Furthermore, dysregulation of the miR-200 family is related to the IL-2 expression level, and it has been confirmed with transfection of miR-200c to triplenegative breast cancer cells (TNBC) that decreased the IL-2 expression level. ...
miR‐200c‐3p is demonstrated to play the role of tumour suppressor in different tumours. However, the miR‐200c‐3p biological function in normal fibroblast (NF) and cancer‐associated fibroblast (CAF) remains unclear. This investigation aims to study the regulatory role of miR‐200c‐3p in the secretion of Interleukin‐2 (IL‐2) in CAF and NF. CAFs and NFs were isolated from tumour and normal tissue specimens respectively. Immunocytochemistry was used to confirm the presence of a fibroblast specific marker, alpha‐actin smooth muscle, in NFs and CAFs. NF and CAF were transfected with scramble and miR‐200c‐3p utilizing the lipofectamine 2000 reagent. The protein levels of IL‐2 were measured in CAFs, NFs, and transfected groups with miR‐200c‐3p and scrambled using an IL‐2 enzyme‐linked immunoassay kit. miR‐200c decreased secretion of IL‐2 in transfected CAF and NF compared to controls. Results elucidated that transfection of MiR‐200c‐3p can decrease the IL‐2 secretion and consequently reduce IL‐induced tumourigenic manner in the CAF. MiR‐200c‐3p transfection decreases the Interleukin‐2 (IL‐2) secretion level, resulting in a reduction in IL‐induced tumourigenic manner of cancer‐associated fibroblast.
... For instance, IL9 inhibited the proliferation of the gastric cancer cell line SGC-7901 in vitro (Cai et al., 2019) through the activation of adaptive or innate immune responses. However, IL9 can act as a tumorigenic factor or an enhancing factor to promote the proliferation of hematological tumors and some solid tumors (Chen and Wang, 2014;Hu et al., 2017). CD96 is mainly involved in immune function, especially the immune response mediated by T cells. ...
The clinical outcome of heterogeneous bladder cancer (BCa) is impacted by varying molecular characteristics and clinical features, and new molecular classification is necessary to recognize patients with dichotomized prognosis. We enrolled a total of 568 BCa patients from the TCGA-BLCA and GSE13507 cohorts. A total of 107 candidate genes, which were mostly involved in the extracellular matrix-associated pathway, were first selected through the consensus value of the area under the receiver operating characteristic curve (AUC). Furthermore, absolute shrinkage and selection operation regression analysis was implemented to reveal the 15 genes and establish the prognostic signature. The newly defined prognostic signature could precisely separate BCa patients into subgroups with favorable and poor prognosis in the training TCGA-BLCA cohort (p < 0.001, HR = 2.41, and 95% CI: 1.76–3.29), as well as the testing GSE13507 cohort (p < 0.001, HR = 7.32, and 95% CI: 1.76–3.29) and external validation E-MTAB-4321 cohort (p < 0.001, HR = 10.56, 95% CI: 3.208–34.731). Multivariate Cox analysis involving the signature and clinical features indicated that the signature is an independent factor for the prediction of BCa prognosis. We also explored potential targeted therapy for BCa patients with high- or low-risk scores and found that patients with high risk were more suitable for chemotherapy with gemcitabine, doxorubicin, cisplatin, paclitaxel, and vinblastine (all p < 0.05), but anti-PD-L1 therapy was useless. We knocked down HEYL with siRNAs in T24 and 5,637 cells, and observed the decreased protein level of HEYL, and inhibited cell viability and cell invasion. In summary, we proposed and validated a 15-top-prognostic gene-based signature to indicate the dichotomized prognosis and response to targeted therapy.
... Indeed, IL-9 may exert a pro-tumorigenic activity through the interaction with microRNAs (miRNAs). IL-9 treatment of pancreatic cancer cell lines was found to increase their proliferation and metastatic properties through the modulation of the miR-200a/β-catenin axis [93]. Moreover, miR-208b-5p was found to target the 3 untranslated region of IL-9 and to inhibit the STAT3 pathway in non-small cell lung cancer cells [94], thus inhibiting their invasive and migratory capacities. ...
Pseudomyxoma Peritonei (PMP) is an anatomo-clinical condition characterized by the implantation of neoplastic cells on peritoneal surfaces with the production of a large amount of mucin. The rarity of the disease precludes the evaluation of treatment strategies within randomized controlled trials. Cytoreductive Surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has proven to be the only therapeutic option with potential chances of cure and long-term disease control. The present review discusses the epidemiology, pathogenesis, clinical presentation and treatment of PMP, focusing on the molecular factors involved in tumor progression and mucin production that could be used, in the upcoming future, to improve patient selection for surgery and to expand the therapeutic armamentarium.
... Previous studies have shown that IL-9 promotes cell proliferation [33,34]. Lung fibroblasts, the major effector cells of the progressive fibrotic process in IPF, secrete excess extracellular matrix, and eventually lead to pulmonary fibrosis. ...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced lung fibrosis mice. Moreover, we found that Th9 cells promote pulmonary fibrosis in two ways. On the one hand, Th9 cells promote fibroblast differentiation, activation, and collagen secretion by secreting IL-9. On the other hand, they promote differentiation of Th0 cells into Th2 cells by secreting IL-4. Th9 cells and Th2 cells can promote each other, accelerating the Th1/Th2 imbalance and eventually forming a positive feedback of pulmonary fibrosis. In addition, we found that neutralizing IL-9 in both preventive and therapeutic settings ameliorates bleomycin-induced pulmonary fibrosis. Furthermore, we identified several critical signaling pathways involved in the effect of neutralizing IL-9 on pulmonary fibrosis by proteomics study. From an immunological perspective, we elucidated the novel role and underlying mechanism of Th9 cells in pulmonary fibrosis. Our study suggested that Th9-based immunotherapy may be employed as a treatment strategy for IPF.
... IL-6 is associated with an aggressive PCa phenotype by inducing VEGF, promoting tumor cell proliferation, suppressing apoptosis, and driving Th cell differentiation of regulatory Th cells (64). IL-9 has both anti-and pro-tumor actions that are not well understood (65), and IL-9 has complicated anti-tumor and pro-tumor properties mediated by innate and adaptive immunity (66), including in PCa (67). In RM-9 tumors from stressed groups, IL-6, and IL-9 expression was greater in old than in young mice ( Figures 7C, D, respectively; Figure 7C: *, p<0.05; Figure 7D: *, p<0.05). ...
Prostate cancer (PCa) prevalence is higher in older men and poorer coping with psychosocial stressors effect prognosis. Yet, interactions between age, stress and PCa progression are underexplored. Therefore, we characterized the effects of age and isolation combined with restraint (2 h/day) for 14 days post-tumor inoculation on behavior, tumor growth and host defense in the immunocompetent, orthotopic RM-9 murine PCa model. All mice were tumor inoculated. Isolation/restraint increased sympathetic and hypothalamic-pituitary-adrenal cortical activation, based on elevated serum 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratios and corticosterone levels, respectively. Elevated zero maze testing revealed age-related differences in naïve C57Bl/6 mice, and increased anxiety-like behavior in tumor-bearing mice. In open field testing, old stressed mice were less active throughout the 30-min test than young non-stressed and stressed, and old non-stressed mice, suggesting greater anxiety in old stressed mice. Old (18 month) mice demonstrated more depression-like behavior than young mice with tail suspension testing, without effects of isolation/restraint stress. Old mice developed larger tumors, despite similar tumor expression of tumor vascular endothelial growth factor or transforming growth factor-beta1 across age. Tumor chemokine/cytokine expression, commonly prognostic for poorer outcomes, were uniquely age- and stress-dependent, underscoring the need for PCa research in old animals. Macrophages predominated in RM-9 tumors. Macrophages, and CD4⁺ and CD4⁺FoxP3⁺ T-cell tumor infiltration were greater in young mice than in old mice. Stress increased macrophage infiltration in old mice. Conversely, stress reduced intratumoral CD4⁺ and CD4⁺FoxP3⁺ T-cell numbers in young mice. CD8⁺ T-cell infiltration was similar across treatment groups. Our findings support that age- and psychological stress interacts to affect PCa outcomes by interfering with neural-immune mechanisms and affecting behavioral responses.
... 12 MiR-200a is induced by a range of physiological stimuli, including IL-9, that enhances miR-200a/β-Catenin expression and subsequent cancer cell metastasis. 13 Low levels of miR-93 and miR-200a expression in cancer cells are also associated with a loss of differentiation in PDAC, 14 while its overexpression enhances chemo-resistance and MT1-MMP expression in PC cells. 15,16 MiR-200a can inhibit PC metastasis through its ability to suppress DEK. 17 In our previous studies, we confirmed that miR-200a is suppressed in PC stem cells 18 but the involvement of TP73-AS1 was not reported. ...
Pancreatic ductal adenocarcinoma (PDAC) is an invasive and aggressive cancer that remains a major threat to human health across the globe. Despite advances in cancer treatments and diagnosis, the prognosis of PDAC patients remains poor. New and more effective PDAC therapies are therefore urgently required. In this study, we identified a novel host factor, namely the LncRNA TP73‐AS1, as overexpressed in PDAC tissues compared to adjacent healthy tissue samples. The overexpression of TP‐73‐AS1 was found to correlate with both PDAC stage and lymph node metastasis. To reveal its role in PDCA, we targeted TP73‐AS1 using LnRNA inhibitors in a range of pancreatic cancer (PC) cell lines. We found that the inhibition of TP73‐AS1 led to a loss of MMP14 expression in PC cells and significantly inhibited their migratory and invasive capacity. No effects of TP73‐AS1 on cell survival or proliferation were observed. Mechanistically, we found that TP73‐AS1 suppressed the expression of the known oncogenic miR‐200a. Taken together, these data highlight the prognostic potential of TP73‐AS1 for PC patients and highlight it as a potential anti‐PDAC therapeutic target.
... It has been generally suggested that IL9 may inhibit the growth of solid tumors by activating the innate or adaptive immune response [425,426], while as a lymphocyte growth factor, it may promote the progression of hematological malignancies [253,408]. However, since IL9 has also been reported to promote the proliferation of multiple solid tumor models (like pancreatic cancer, lung cancer, and colitis-associated cancer) [427][428][429], ...
Multispecific molecules based on proteins or peptides represent a new generation of targeted biopharmaceuticals that hold great therapeutic promise. Engineered biotherapeutics drugs offer the possibility to combine multiple molecules with specific therapeutic functions featuring additional therapeutic activities, selective localization to the site of the disease and possibly extended half-life. Targeting disease-specific antigens with antibodies or small molecules has been an extensively explored strategy to selectively deliver therapeutically active payloads (e.g., cytokines, cytotoxic drugs or radionuclides) to the site of disease. The target antigen choice is of crucial importance for the successful development of targeted drugs. Alternative splice isoforms of fibronectin, such as the ones containing the extra-domain A (EDA), are extracellular matrix markers of tissue remodeling. EDA is overexpressed in different pathological conditions, including cancer and inflammatory diseases, but it is virtually absent from adult healthy tissues. Similarly, carbonic anhydrase IX (CAIX) is a cell surface tumor-associated antigen, which is overexpressed in 90% of renal cell carcinomas, but in healthy tissues his pattern of expression pattern is highly restricted to some gastrointestinal structures. Both EDA and CAIX represent excellent molecular targets for pharmacodelivery applications. Over the past two decades, a variety of cytokines or bioactive molecules have been fused to antibodies (e.g., immunocytokines and antibody drug conjugates) and small molecules (e.g., small molecule drug conjugates), in order to improve their therapeutic properties. Some of these bifunctional therapeutics have shown promising preclinical efficacy and have been further investigated in clinical trials for a variety of pathological conditions. In this thesis, we used different methodologies to generate bifunctional therapeutics and performed initial evaluations of their therapeutic and pharmacokinetic properties. Prompted by the postulated activity of interleukin 9 (IL9) in tumor immunity and resolution of chronic inflammation in arthritis, we have genetically engineered antibody-cytokine fusion proteins (immunocytokines) based on IL9 and the F8 antibody, which specifically recognize the EDA domain of fibronectin. An immunocytokine variant showing improved in vivo targeting efficacy was further tested for therapeutic efficacy in various preclinical disease models. In a second approach we have investigated the possibility of using small molecular ligands as targeting moieties for the pharmacodelivery of cytokines. To this aim we used the Sortase A enzyme to catalyze the covalent linkage between moieties containing specific peptidic sequences. The obtained product, termed AAZ-IL2, consisted in the fusion between acetazolamide, a CAIX ligand, and interleukin-2. Whereas AAZ-IL2 retained CAIX binding activity in vitro, it demonstrated only modest in vivo targeting efficacy. Finally, we used a chemical assembly approach to generate a fusion molecule between a therapeutic peptide and a small molecule specific to human and mouse Albumin. Due to small size, peptides have very short half-life which limits their therapeutic use. To improve the pharmacokinetics of therapeutics, Albumin represents an attractive target, due to its very high abundance in blood. Albutag, a small ligand that selectively targets specific to Albumin, has been previously used to extend the half-life of various payloads. With the aim of enhancing the pharmacokinetic properties of a therapeutically relevant peptide, we have generated a new peptide-Albutag fusion molecule, and characterized it in vitro for Albumin binding affinity and in vivo for pharmacokinetic properties. Altogether the research presented in this thesis may be of significance for the further development of bifunctional biopharmaceuticals with improved therapeutic and pharmaceutical properties.
