Cytokines In Tumor Microenvironment Research Articles

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy.

Liver cancer is the third leading of tumor death, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors (ICIs) are yielding much for sufferers to hope for patients, but only some patients with advanced liver tumor respond. Recent research showed that tumor microenvironment (TME) is critical for the effectiveness of ICIs in advanced liver tumor. Meanwhile, metabolic reprogramming of liver tumor leads to immunosuppression in TME. These suggest that regulating the abnormal metabolism of liver tumor cells and firing up TME to turn "cold tumor" into "hot tumor" are potential strategies to improve the therapeutic effect of ICIs in liver tumor. Previous studies have found that YAP1 is a potential target to improve the efficacy of anti-PD-1 in HCC. Here, we review that YAP1 promotes immunosuppression of TME, mainly due to the overstimulation of cytokines in TME by YAP1. Subsequently, we studied the effects of YAP1 on metabolic reprogramming in liver tumor cells, including glycolysis, gluconeogenesis, lipid metabolism, arachidonic acid metabolism, and amino acid metabolism. Lastly, we summarized the existing drugs targeting YAP1 in the treatment of liver tumor, including some medicines from natural sources, which have the potential to improve the efficacy of ICIs in the treatment of liver tumor. This review contributed to the application of targeted YAP1 for combined therapy with ICIs in liver tumor patients.

Understanding the regulation of "Don't Eat-Me" signals by inflammatory signaling pathways in the tumor microenvironment for more effective therapy.

Receptor/ligand pair immune checkpoints are inhibitors that regulate immunity as vital "Don't Find-Me" signals to the adaptive immune system, additionally, the essential goals of anti-cancer therapy. Moreover, the immune checkpoints are involved in treatment resistance in cancer therapy. The immune checkpoints as a signal from "self" and their expression on healthy cells prevent phagocytosis. Cells (e.g., senescent and/or apoptotic cells) with low immune checkpoints, such as low CD47 and/or PD-L1, are phagocytosed, which is necessary for tissue integrity and homeostasis maintenance. In other words, cancer cells induce increased CD47 expression in the tumor microenvironment (TME), avoiding their clearance by immune cells. PD-L1 and/or CD47 expression tumors have also been employed as biomarkers to guide cure prospects. Thus, targeting innate and adaptive immune checkpoints might improve the influence of the treatments on tumor cells. However, the CD47 regulation in the TME stands intricate, so much of this process has stayed a riddle. In this line, less attention has been paid to cytokines in TME. Cytokines are significant regulators of tumor immune surveillance, and they do this by controlling the actions of the immune cell. Recently, it has been suggested that different types of cytokines at TME might cooperate with others that contribute to the regulation of CD47 and/or PD-L1. The data were searched in available databases and a Web Search engine (PubMed, Scopus, and Google Scholar) using related keywords in the title, abstract, and keywords. Given the significant role of pro/anti-inflammatory signaling in the TME, we discuss the present understanding of pro/anti-inflammatory signaling implications in "Don't Eat-Me" regulation signals, particularly CD47, in the pathophysiology of cancers and come up with innovative opinions for the clinical transformation and personalized medicine.

Dual role of cytokines in tumor microenvironment

Dual role of cytokines in tumor microenvironment

Construction of tandem diabody (IL-6/CD20)-secreting human umbilical cord mesenchymal stem cells and its experimental treatment on diffuse large B cell lymphoma

BackgroundMore than 40% patients with diffuse large B cell lymphoma (DLBCL) experienced relapse or refractory (R/R) lymphoma after the standard first R-CHOP therapy. IL-6 was reportedly associated with chemotherapy resistance of rituximab. Further, mesenchymal stem cells (MSCs) are known as the potential cell vehicle for their tropism toward tumor. A MSCs-based tandem diabody for treating DLBCL is currently lacking.MethodsWe constructed a tandem diabody (Tandab(IL-6/CD20)) with modified umbilical cord MSCs (UCMSCs) and designed a cell-based Tandab releasing system. Western blot, qPCR and immunofluorescence were used to confirm the construction and expression of lentivirus-infected UCMSCs. The vitality, apoptosis and homing abilities of UCMSCs were examined via CCK-8 assay, apoptosis, wound healing and migration analysis. Cell binding assay was used to demonstrate the targeting property of Tandab binding to CD20-positive DLBCL cells. Furthermore, we evaluated the viability of SU-DHL-2 and SU-DHL-4 by using CCK-8 and EDU assay after the treatment of UCMSCs-Tandab(IL-6/CD20).ResultsTandab protein peaked at 6273 ± 487 pg/ml in the medium on day 7 after cell culture. The proliferation and homing ability of UCMSCs did not attenuate after genetically modification. Immunofluorescence images indicated the Tandab protein bound to the lymphoma cells. UCMSCs-Tandab(IL-6/CD20) inhibited the growth of SU-DHL-2 or SU-DHL-4 cells in vitro.ConclusionsUCMSCs-Tandab(IL-6/CD20), which bound with both tumor-associated surface antigens and pro-tumor cytokines in tumor microenvironment, might serve as a potential treatment for DLBCL, evidenced by inhibiting the growth of SU-DHL-2 or SU-DHL-4 cells.

Dual Function of Secreted APE1/Ref-1 in TNBC Tumorigenesis: An Apoptotic Initiator and a Regulator of Chronic Inflammatory Signaling.

The simultaneous regulation of cancer cells and inflammatory immune cells in the tumor microenvironment (TME) can be an effective strategy in treating aggressive breast cancer types, such as triple-negative breast cancer (TNBC). Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multi-functional nuclear protein that can be stimulated and then secreted. The extracellular APE1/Ref-1 causes a reduction in disulfide bonds in cytokine receptors, resulting in their conformational changes, thereby inhibiting inflammatory signaling. Furthermore, the secreted APE1/Ref-1 in response to acetylation has been shown to bind to a receptor for the advanced glycation end product (RAGE), initiating the apoptotic cell death of TNBC in vitro and in vivo. This study used PPTLS-APE1/Ref-1 in an adenovirus vector (Ad-PPTLS-APE1/Ref-1) for the constant expression of extracellular APE1/Ref-1, and our results demonstrated its dual function as an apoptotic initiator and inflammation regulator. Injecting MDA-MB 231 orthotopic xenografts with the Ad-PPTLS-APE1/Ref-1 inhibited tumor growth and development in response to acetylation. Moreover, Ad-PPTLS-APE1/Ref-1 generated reactive oxygen species (ROS), and tumor tissues derived from these xenografts exhibited apoptotic bodies. Compared to normal mice, a comparable ratio of anti- and pro-inflammatory cytokines was observed in the plasma of Ad-PPTLS-APE1/Ref-1-injected mice. Mechanistically, the disturbed cytokine receptor by reducing activity of PPTLS-APE1/Ref-1 inhibited inflammatory signaling leading to the inactivation of the p21-activated kinase 1-mediated signal transducer and activator of transcription 3/nuclear factor-κB axis in tumor tissues. These results suggest that the regulation of inflammatory signaling with adenoviral-mediated PPTLS-APE1/Ref-1 in tumors modulates the secretion of pro-inflammatory cytokines in TME, thereby inhibiting aggressive cancer cell progression, and could be considered as a promising and safe therapeutic strategy for treating TNBCs.

Role of Interleukins and New Perspectives in Mechanisms of Resistance to Chemotherapy in Gastric Cancer.

Gastric cancer (GC) is the fourth most common cancer in the world in terms of incidence and second in terms of mortality. Chemotherapy is the main treatment for GC. The greatest challenge and major cause of GC treatment failure is resistance to chemotherapy. As such, research is ongoing into molecular evaluation, investigating mechanisms, and screening therapeutic targets. Several mechanisms related to both the tumor cells and the tumor microenvironment (TME) are involved in resistance to chemotherapy. TME promotes the secretion of various inflammatory cytokines. Recent studies have revealed that inflammatory cytokines affect not only tumor growth, but also chemoresistance. Cytokines in TME can be detected in blood circulation and TME cells. Inflammatory cytokines could serve as potential biomarkers in the assessment of chemoresistance and influence the management of therapeutics in GC. This review presents recent data concerning research on inflammatory cytokines involved in the mechanisms of chemoresistance and provides new clues in GC treatment.

Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers.

B cells are well known as key mediators of humoral immune responses via the production of antibodies. Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and provides the first line of immune protection at mucosal surfaces. However, IgA has long been a divisive molecule with respect to tumor progression. IgA exerts anti- or pro-tumor effect in different tumor types. In this review, we summarize emerging evidence regarding the production and effects of IgA and IgA+ cells in the tumor microenvironment (TME). Moreover, we discuss that the TME cytokines, host diet, microbiome, and metabolites play a pivotal role in controlling the class-switch recombination (CSR) of IgA. The analysis of intratumoral Ig repertoires and determination of metabolites that influence CSR may help establish novel therapeutic targets for the treatment of cancers.

PD05-04 INCREASED NITRIC OXIDE SUPPRESSES MACROPHAGE POLARIZATION TO AUGMENT THE EFFECT OF CSFR1 INHIBITION THERAPY AGAINST CASTRATION RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I (PD05)1 Sep 2021PD05-04 INCREASED NITRIC OXIDE SUPPRESSES MACROPHAGE POLARIZATION TO AUGMENT THE EFFECT OF CSFR1 INHIBITION THERAPY AGAINST CASTRATION RESISTANT PROSTATE CANCER Fakiha Firdaus, Manish Kuchakulla, Yash Soni, Rehana Qureshi, Derek J. Van Booven, Khushi Shah, Omar Joel Rosete, Joshua M. Hare, Ranjith Ramasamy, and Himanshu Arora Fakiha FirdausFakiha Firdaus More articles by this author , Manish KuchakullaManish Kuchakulla More articles by this author , Yash SoniYash Soni More articles by this author , Rehana QureshiRehana Qureshi More articles by this author , Derek J. Van BoovenDerek J. Van Booven More articles by this author , Khushi ShahKhushi Shah More articles by this author , Omar Joel RoseteOmar Joel Rosete More articles by this author , Joshua M. HareJoshua M. Hare More articles by this author , Ranjith RamasamyRanjith Ramasamy More articles by this author , and Himanshu AroraHimanshu Arora More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001969.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is one of the most common non-skin cancers prevailing in American males. Targeting the tumor microenvironment (TME) using colony stimulating factor 1 (CSF1R) inhibition is a promising therapy for castration-resistant prostate cancer (CRPC). However, the therapeutic response to sustained CSF1R blockade therapy (CSF1Ri) is limited as a monotherapy. In our previous studies, we demonstrated that increased nitric oxide (NO) using S-nitrosoglutathione (GSNO) suppresses the prostate cancer TME by indirectly modulating macrophage differentiation and reducing CRPC tumor burden. In this study, we investigated how increased NO augments the action of CSF1Ri against CRPC TME. METHODS: GW2580, a CSF1-receptor inhibitor was tested in-vitro as well as in-vivo, singularly and in combination with S-nitrosoglutathione (GSNO), an active NO donor. In-vivo dosage of 40mg/kg/day for GW2580 and 10mg/kg/day for GSNO were used. For evaluating the effects of treatment on macrophage polarization, U937 cells were exposed to conditioned media from 22RV1 cells, treated with NO, CSF1Ri, or combination of NO-CSF1Ri. Macrophage markers were also checked in tumor grafts using immunohistochemistry. Moreover, we evaluated the percentage of T-regs (CD4+FOXP3+) and myeloid-derived suppressor cells (MDSCs) using flow cytometry. Cytokine antibody array was performed for differential expression in treatment conditions. RESULTS: We observed that NO-CSF1Ri combination decreases CRPC tumor burden compared to NO or CSF1Ri monotherapies. Importantly, we found that the NO-CSF1Ri combination decreases the population of T-regs (CD4+FOXP3+) and myeloid-derived suppressor cells (MDSCs), inhibits the transformation of monocytes into anti-inflammatory macrophages (CD206, F4/80); thus suggesting macrophage polarization to be the mechanism of action for the NO-CSF1Ri combination. Furthermore, cytokine screening suggested that NO-CSF1Ri suppresses several important TME cytokines like IL-12, oncostatin, BLC, FGF4, GCP2, IGFBP3, IP-10, and TGFB3. Interestingly, these cytokines were minimally suppressed by CSF1Ri therapy. Taken together, these results suggest that targeting macrophage polarization via increasing NO is a promising strategy to augment the anti-tumor effects of CSF1Ri alone. CONCLUSIONS: Our findings demonstrated a direct role of increased NO-based immunotherapy to augment the action of CSF1R inhibition to suppress the macrophage polarization in in-vivo models for castration resistant prostate cancer. Source of Funding: Supported by the American Urological Association Research Scholar Award and Stanley Glaser Award to HA and in part by Clinician Scientist Development Award from American Cancer Society to RR. JMH is supported by NIH grants 1R01 HL137355, 1R01 HL107110, 1R01 HL134558, 5R01 CA136387, and 5UM1 HL113460, and the Soffer Family Foundation © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e56-e57 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fakiha Firdaus More articles by this author Manish Kuchakulla More articles by this author Yash Soni More articles by this author Rehana Qureshi More articles by this author Derek J. Van Booven More articles by this author Khushi Shah More articles by this author Omar Joel Rosete More articles by this author Joshua M. Hare More articles by this author Ranjith Ramasamy More articles by this author Himanshu Arora More articles by this author Expand All Advertisement Loading ...

T Cell Exhaustion and CAR-T Immunotherapy in Hematological Malignancies.

T cell exhaustion has been recognized to play an immunosuppressive role in malignant diseases. Persistent tumor antigen stimulation, the presence of inhibitory immune cells and cytokines in tumor microenvironment (TME), upregulated expression of inhibitory receptors, changes in T cell-related transcription factors, and metabolic factors can all result in T cell exhaustion. Strategies dedicated to preventing or reversing T cell exhaustion are required to reduce the morbidity from cancer and enhance the effectiveness of adoptive cellular immunotherapy. Here, we summarize the current findings of T cell exhaustion in hematological malignancies and chimeric antigen receptor T (CAR-T) immunotherapy, as well as the value of novel technologies, to inverse such dysfunction. Our emerging understanding of T cell exhaustion may be utilized to develop personalized strategies to restore antitumor immunity.

Immune cell infiltration and cytokine secretion analysis reveal a non-inflammatory microenvironment of medulloblastoma.

Medulloblastoma (MB) is the most common lethal malignant pediatric brain tumor. Adjuvant immunotherapy for medulloblastoma has been proposed in both pre-clinical and clinical practice. To provide a precision strategy of designing immunotherapy for MB, the present study performed a descriptive analysis of immune microenvironment in a cohort and compared the differences between four subgroups of MB. Subtypes (WNT, SHH Group 3 and Group 4) of medulloblastoma were identified using K-means clustering according to the expression of signature genes. Tumor infiltrating immune cell population was assessed by both bio-informative algorithm based on gene expression and immunohistochemistry staining. Cytokines in tumor microenvironment were detected using Luminex. Gene Set Enrichment Analysis demonstrated a raised immune response in the SHH subgroup. Lymphocyte infiltration was low in all four subgroups, while more CD4+ T cells were observed in the Group 4 subtype. Programmed cell death protein 1 (PD1)/ ligand 1 (PD-L1) expression was absent in the cohort. The SHH subtype recruited more activated tumor associated macrophage/microglia compared with the other subgroups. Cytokines within the MB microenvironment were low compared with the glioblastoma samples. In contrast to glioblastoma, the immune microenvironment of pediatric MB is non-inflammatory and does not recruit many immune cells. These observations provide important considerations for the design of immunotherapeutic approaches for MB, such as inducing more lymphocytes into the tumor microenvironment.

Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/β-Catenin Signaling.

Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and β-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.

HDAC9 deficiency promotes tumor progression by decreasing the CD8+ dendritic cell infiltration of the tumor microenvironment

BackgroundThe tumor microenvironment (TME) contains a variety of immune cells, which play critical roles during the multistep development of tumors. Histone deacetylase 9 (HDAC9) has been reported to have either...

Interleukin-17 promotes nitric oxide-dependent expression of PD-L1 in mesenchymal stem cells

BackgroundInterleukin-17A (IL-17) is an evolutionary conserved cytokine and best known for its role in boosting immune response. However, recent clinical researches showed that abundant IL-17 in tumor microenvironment was often associated with poor prognosis and reduced cytotoxic T cell infiltration. These contradictory phenomena suggest that IL-17 may have unique target cells in tumor microenvironment which switch its biological consequences from pro-inflammatory to anti-inflammatory. Mesenchymal stem/stromal cells (MSCs) are a major component of the tumor microenvironment. Upon cytokine stimulation, MSCs can express a plenary of inhibitory molecules, playing a critical role in tumor development and progression. Therefore, we aim to investigate the role of IL-17 in MSC-mediated immunosuppression.ResultsWe found IFNγ and TNFα, two major cytokines in tumor microenvironment, could induce programmed death-ligand 1 (PD-L1) expression in MSCs. Interestingly, IL-17 has a synergistic effect with IFNγ and TNFα in elevating PD-L1 expression in MSCs. The presence of IL-17 empowered MSCs with strong immunosuppression abilities and enabled MSCs to promote tumor progression in a PD-L1 dependent manner. The upregulated PD-L1 expression in MSCs was due to the accumulation of nitric oxide (NO). On one hand, NO donor could mimic the effects of IL-17 on MSCs; on the other hand, IL-17 failed to enhance PD-L1 expression in inducible nitric oxide synthase (iNOS) deficient MSCs or with iNOS inhibitor presence.ConclusionsOur study demonstrates that IL-17 can significantly increase the expression of PD-L1 by MSCs through iNOS induction. This IL-17-MSCs-PD-L1 axis shapes the immunosuppressive tumor microenvironment and facilitates tumor progression.

CCL20 Signaling in the Tumor Microenvironment.

CCL20, as a chemokine, plays an important role in rheumatoid arthritis, psoriasis, and other diseases by binding to its receptor CCR6. Recent 10 years' research has demonstrated that CCL20 also contributes to the progression of many cancers, such as liver cancer, colon cancer, breast cancer, pancreatic cancer, and gastric cancer. This article reviews and discusses the previous studies on CCL20 roles in cancers from the aspects of its specific effects on various cancers, its remodeling on tumor microenvironment (TME), its synergistic effects with other cytokines in tumor microenvironment, and the specific mechanisms of CCL20 signal activation, illustrating CCL20 signaling in TME from multiple directions.

1897P - Interplay between miR-17-5p and MALAT-1 shapes the cytokine storm in triple negative breast cancer (TNBC) tumor microenvironment

BackgroundTNBC is the most immunogenic tumor compared to other BC subtypes. Thus, clinicians shifted the treatment among TNBC patients to immunotherapeutic alternatives such as immune checkpoint inhibitors (ICB). Despite the success of ICB, resistance in some TNBC cases had recently appeared. Thus, adding a new factor in the immunotherpeutic equation which could be the tumor microenvironment (TME); TME includes an array of immune-modulatory cytokines such as Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) that acts as a barrier in eradicating the tumor cells by the cytotoxic immune cells. Recently, our group has reported a novel crosstalk between non-coding RNAs (ncRNAs). MALAT1, an oncogenic long ncRNA, is recently reported to directly bind to microRNA-17-92 cluster. However, miR-17-5p role in TNBC is still controversial. Moreover, the impact of miR-17-5p, MALAT1 and their interplay in the TME has never been investigated. The aim of this study is to investigate the crosstalk between ncRNAs and their impact on cytokines in TME of TNBC cells. MethodsTwenty BC patients were recruited. Bioinformatic analysis was performed using more than 5 softwares. MDA-MB-231 cells were cultured and transfected with miR-17-5p oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability and Colony forming ability were measured using MTT and colony forming assay. ResultsMALAT-1, miR-17-5p and IL-10 were down-regulated while TNF-α was upregulated in BC tissues compared to its counterparts. In-silico analysis showed that miR-17-5p binds to MALAT-1, IL-10 and TNF-α. Experimentally, ectopic expression of miR-17-5p (>5000 folds) resulted in a marked reduction in cellular viability and colony forming ability of TNBC cells. On top of that, miR-17-5p mimics resulted in a significant repression of MALAT1. Consequently, a marked increase in IL-10 and TNF-α levels was shown. While anti-miR-17-5p resulted in a marked repression of IL-10 and TNF-α. ConclusionsmiR-17-5p is an upstream orchestrator of MALAT-1/IL-10/TNF-α shaping the TME in TNBC patients. Therefore, this study provides a novel combination therapeutic approach of Anti-miR-17-5p and ICB with decreased chance of resistance in TNBC patients. Legal entity responsible for the studyGerman University in Cairo. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

The opposing effects of interferon-beta and oncostatin-M as regulators of cancer stem cell plasticity in triple-negative breast cancer

BackgroundHighly aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). Cytokines within the breast tumor microenvironment (TME) influence the CSC state by regulating tumor cell differentiation programs. Two prevalent breast TME cytokines are oncostatin-M (OSM) and interferon-β (IFN-β). OSM is a member of the IL-6 family of cytokines and can drive the de-differentiation of TNBC cells to a highly aggressive CSC state. Conversely, IFN-β induces the differentiation of TNBC, resulting in the repression of CSC properties. Here, we assess how these breast TME cytokines influence CSC plasticity and clinical outcome.MethodsUsing transformed human mammary epithelial cell (HMEC) and TNBC cell models, we assessed the CSC markers and properties following exposure to OSM and/or IFN-β. CSC markers included CD24, CD44, and SNAIL; CSC properties included tumor sphere formation, migratory capacity, and tumor initiation.ResultsThere are three major findings from our study. First, exposure of purified, non-CSC to IFN-β prevents OSM-mediated CD44 and SNAIL expression and represses tumor sphere formation and migratory capacity. Second, during OSM-induced de-differentiation, OSM represses endogenous IFN-β mRNA expression and autocrine/paracrine IFN-β signaling. Restoring IFN-β signaling to OSM-driven CSC re-engages IFN-β-mediated differentiation by repressing OSM/STAT3/SMAD3-mediated SNAIL expression, tumor initiation, and growth. Finally, the therapeutic use of IFN-β to treat OSM-driven tumors significantly suppresses tumor growth.ConclusionsOur findings suggest that the levels of IFN-β and OSM in TNBC dictate the abundance of cells with a CSC phenotype. Indeed, TNBCs with elevated IFN-β signaling have repressed CSC properties and a better clinical outcome. Conversely, TNBCs with elevated OSM signaling have a worse clinical outcome. Likewise, since OSM suppresses IFN-β expression and signaling, our studies suggest that strategies to limit OSM signaling or activate IFN-β signaling will disengage the de-differentiation programs responsible for the aggressiveness of TNBCs.

Breaking the oncostatin M feed-forward loop to suppress metastasis and therapy failure.

Deciphering the complex milieu that makes up the tumor microenvironment (TME) and the signaling engaged by TME cytokines continues to provide novel targets for therapeutic intervention. The IL-6 family member oncostatin M (OSM) has recently emerged as a potent driver of tumorigenesis, metastasis, and therapy failure, molecular programs most frequently attributed to IL-6 itself. In a recent issue of The Journal of Pathology, Kucia-Tran et al describe how elevated oncostatin M receptor (OSMR) expression results in a feed-forward loop involving the de novo production of both OSM and OSMR to facilitate aggressive properties in squamous cell carcinoma (SCC). Here, we discuss how new findings implicating OSM in conferring aggressive cancer cell properties can be leveraged to suppress metastatic outgrowth and therapy failure in SCC as well as other cancers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

RETRACTED ARTICLE: TGF-\u03b22 initiates autophagy via Smad and non-Smad pathway to promote glioma cells\u2019 invasion

BackgroundGlioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood.MethodsU251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.ResultsHere we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better “turn off” tumor growth.ConclusionOur findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion.

Abstract 2892: Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling

Abstract Increasing evidence suggests that tumor cell plasticity promotes metastasis and tumor recurrence, resulting in cancer patient mortality. While it is clear that the tumor microenvironment (TME) contributes to tumor cell plasticity, the specific TME factors that actively generate tumor cell plasticity are largely unknown. Here, we identify TME cytokines that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem-cell (CSC) properties. A screen of 27 TME cytokines identified multiple Interleukin-6 family members as inducers of mesenchymal/CSC properties, with Oncostatin M (OSM) being the most potent. Importantly, OSM induced plasticity was mediated by STAT3, but also dependent on TGF-β signaling and downstream SMAD3. Inhibition of functional TGF-β/SMAD signaling by expressing a dominant-negative TGF-β receptor, treating with a TGF-β receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented the OSM-induced mesenchymal/CSC properties. OSM-activated STAT3 binds to SMAD3 and promotes SMAD3 nuclear localization and binding to the SNAIL promoter, increasing transcription of the SNAIL gene. The epithelial-mesenchymal transition induced by the STAT3/SMAD3 axis results in a highly invasive and metastatic phenotype and the emergence of CSC properties, including therapeutic resistance. Importantly, maintenance of the OSM-induced mesenchymal/CSC state requires sustained exposure to the cytokine, as removal of OSM results in a marked phenotypic reversion. A high-throughput screen for small molecule inhibitors of the OSM-induced mesenchymal/CSC phenotype has been performed and are currently being confirmed. We propose that, targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity associated with metastasis and tumor recurrence. Citation Format: Benjamin L. Bryson, Damian J. Junk, Jacob Smigiel, Neetha Parameswaran, Mary R. Doherty, Courtney A. Bartel, Mark Jackson. Oncostatin M elicits cellular plasticity through cooperative STAT3-SMAD3 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2017-2892

Type 1 Immune Mechanisms Driven by the Response to Infection with Attenuated Rabies Virus Result in Changes in the Immune Bias of the Tumor Microenvironment and Necrosis of Mouse GL261 Brain Tumors.

Immunotherapeutic strategies for malignant glioma have to overcome the immunomodulatory activities of M2 monocytes that appear in the circulation and as tumor-associated macrophages (TAMs). M2 cell products contribute to the growth-promoting attributes of the tumor microenvironment (TME) and bias immunity toward type 2, away from the type 1 mechanisms with antitumor properties. To drive type 1 immunity in CNS tissues, we infected GL261 tumor-bearing mice with attenuated rabies virus (RABV). These neurotropic viruses spread to CNS tissues trans-axonally, where they induce a strong type 1 immune response that involves Th1, CD8, and B cell entry across the blood-brain barrier and virus clearance in the absence of overt sequelae. Intranasal infection with attenuated RABV prolonged the survival of mice bearing established GL261 brain tumors. Despite the failure of virus spread to the tumor, infection resulted in significantly enhanced tumor necrosis, extensive CD4 T cell accumulation, and high levels of the proinflammatory factors IFN-γ, TNF-α, and inducible NO synthase in the TME merely 4 d postinfection, before significant virus spread or the appearance of RABV-specific immune mechanisms in CNS tissues. Although the majority of infiltrating CD4 cells appeared functionally inactive, the proinflammatory changes in the TME later resulted in the loss of accumulating M2 and increased M1 TAMs. Mice deficient in the Th1 transcription factor T-bet did not gain any survival advantage from RABV infection, exhibiting only limited tumor necrosis and no change in TME cytokines or TAM phenotype and highlighting the importance of type 1 mechanisms in this process.