scholarly journals Combination immunotherapy using G-CSF and oncolytic virotherapy reduces tumor growth in osteosarcoma

2021 ◽  
Vol 9 (3) ◽  
pp. e001703
Author(s):  
Alvaro Morales-Molina ◽  
Stefano Gambera ◽  
Angela Leo ◽  
Javier García-Castro
Keyword(s):  
Tumor Growth ◽  
Immune Cells ◽  
Survival Rates ◽  
Tumor Infiltrating Lymphocytes ◽  
Good Prognosis ◽  
Oncolytic Virotherapy ◽  
Immune Infiltration ◽  
Oncolytic Adenoviruses ◽  
Malignant Solid Tumor

BackgroundOsteosarcoma is the most common malignant solid tumor that affects bones, however, survival rates of patients with relapsed osteosarcoma have not improved in the last 30 years. Oncolytic virotherapy, which uses viruses designed to selectively replicate in cancer cells, has emerged as a promising treatment for solid tumors. Our group uses mesenchymal stem cells (MSCs) to transport oncolytic adenoviruses (OAds) to the tumor site, a therapeutic strategy called Celyvir. This treatment has been already applied in human patients, canine patients and different mouse models. In parallel, previous results have probed that administration of granulocyte-colony stimulating factor (G-CSF) increased immune infiltration in tumors. We then hypothesized that the mobilization of immune cells by G-CSF may increase the antitumor efficacy of Celyvir treatment by increasing the immune infiltration into the tumors.MethodsIn this study, we use a murine version of Celyvir consisting in murine MSCs carrying the murine OAd dlE102—here called OAd-MSCs—in an immunocompetent model of osteosarcoma. We tested the antitumoral efficacy of the combination of OAd-MSCs plus G-CSF.ResultsOur results show that treatment with OAd-MSCs or the union of OAd-MSCs with G-CSF (Combination) significantly reduced tumor growth of osteosarcoma in vivo. Moreover, treated tumors presented higher tumor infiltration of immune cells—especially tumor-infiltrating lymphocytes—and reduced T cell exhaustion, which seems to be enhanced in tumors treated with the Combination. The comparison of our results to those obtained from a cohort of pediatric osteosarcoma patients showed that the virotherapy induces immunological changes similar to those observed in patients with good prognosis.ConclusionsThe results open the possibility of using cellular virotherapy for the treatment of bone cancers. Indeed, its combination with G-CSF may be considered for the improvement of the therapy.

scholarly journals Combinations of TLR Ligands: A Promising Approach in Cancer Immunotherapy

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Saskia Stier ◽  
Claudia Maletzki ◽  
Ulrike Klier ◽  
Michael Linnebacher
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
Immune Cells ◽  
Human Lymphocytes ◽  
Growth Control ◽  
Poly I:C ◽  
The Impact

Toll-like receptors (TLRs), a family of pattern recognition receptors recognizing molecules expressed by pathogens, are typically expressed by immune cells. However, several recent studies revealed functional TLR expression also on tumor cells. Their expression is a two-sided coin for tumor cells. Not only tumor-promoting effects of TLR ligands are described but also direct oncopathic and immunostimulatory effects. To clarify TLRs’ role in colorectal cancer (CRC), we tested the impact of the TLR ligands LPS, Poly I:C, R848, and Taxol on primary human CRC cell lines (HROC40, HROC60, and HROC69)in vitroandin vivo(CT26). Taxol, not only a potent tumor-apoptosis-inducing, but also TLR4-activating chemotherapeutic compound, inhibited growth and viability of all cell lines, whereas the remaining TLR ligands had only marginal effects (R848 > LPS > Poly I:C). Combinations of the substances here did not improve the results, whereas antitumoral effects were dramatically boosted when human lymphocytes were added. Here, combining the TLR ligands often diminished antitumoral effects.In vivo, best tumor growth control was achieved by the combination of Taxol and R848. However, when combined with LPS, Taxol accelerated tumor growth. These data generally prove the potential of TLR ligands to control tumor growth and activate immune cells, but they also demonstrate the importance of choosing the right combinations.

scholarly journals Neuronal Repressor REST Controls Ewing Sarcoma Growth and Metastasis by Affecting Vascular Pericyte Coverage and Vessel Perfusion

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1405
Author(s):  
Zhichao Zhou ◽  
Yuanzheng Yang ◽  
Fei Wang ◽  
Eugenie S. Kleinerman
Keyword(s):  
Tumor Growth ◽  
Ewing Sarcoma ◽  
Vascular Function ◽  
Fusion Gene ◽  
Critical Role ◽  
Survival Rates ◽  
Tumor Vasculature ◽  
Tumor Growth And Metastasis

Survival rates for Ewing sarcoma (ES) patients with metastatic disease have not improved in over 20 years. Tumor growth and metastasis are dependent on tumor vasculature expansion; therefore, identifying the regulators that control this process in ES may provide new therapeutic opportunities. ES expresses high levels of repressor element 1 silencing transcription factor (REST), which is regulated by the EWS-FLI-1 fusion gene. However, the role of REST in ES growth and the regulation of the tumor vasculature have not been elucidated. To study this role, we established REST-knockout human TC71 ES cell lines through CRISPR/Cas9 recombination. While knockout of REST did not alter tumor cell proliferation in vitro, REST knockout reduced tumor growth and metastasis to the lung in vivo and altered tumor vascular morphology and function. Tumor vessels in the REST-knockout tumors had a punctate appearance with significantly decreased tumor vascular pericytes, decreased perfusion, and increased permeability. REST-knockout tumors also showed increased apoptosis and hypoxia. These results indicate that REST plays a critical role in ES vascular function, which in turn impacts the ability of ES tumors to grow and metastasize. These findings therefore provide a basis for the targeting of REST as a novel therapeutic approach in ES.

scholarly journals P2.03a-048 The CDK4/6 Inhibitor G1T28 Protects Immune Cells from Cisplatin-Induced Toxicity in vivo and Inhibits SCLC Tumor Growth

2017 ◽  
Vol 12 (1) ◽  
pp. S918 ◽  
Author(s):  
Irene Guijarro ◽  
Alissa Poteete ◽  
Renata Ferrarotto ◽  
Warren Denning ◽  
Haifa Hamdi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Cells

scholarly journals TMOD-16. A NOVEL ADENOVIRAL-PERMISSIVE, IMMUNOCOMPETENT HAMSTER GLIOMA MODEL TO EVALUATE ONCOLYTIC ADENOVIRAL THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii231-ii231
Author(s):  
Lynette Phillips ◽  
Joy Gumin ◽  
Shoudong Li ◽  
Marc Daou ◽  
Daniel Ledbetter ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Replication ◽  
Tumor Infiltrating Lymphocytes ◽  
Peripheral Blood Lymphocytes ◽  
T Antigen ◽  
Sv40 Large T Antigen ◽  
Oncolytic Adenoviruses ◽  
Glioma Model

Abstract Oncolytic adenoviruses, including Delta-24-RGD, target tumors by direct tumor cell oncolysis and by activation of an anti-tumor immune response. Due to the species selectivity of oncolytic adenoviruses, there is currently no single preclinical animal model of glioma that supports viral replication, tumor oncolysis, and virus-mediated immune responses. To address this gap, we took advantage of the Syrian hamster to develop the first glioma model that is both adenovirus replication-permissive and immunocompetent. Hamster glioma stem-like cells (GSCs), transformed by forced expression of hTERT, SV40 large T antigen, and h-RasV12, reproducibly form intracranial tumors in hamsters. In vitro, electron microscopy and cytopathic effect assays demonstrated that hamster GSCs supported viral replication and were susceptible to Delta-24-RGD-mediated cell death. In vivo, hamster GSCs consistently developed into highly proliferative tumors resembling high-grade gliomas. Following intratumoral delivery of Delta-24-RGD, immunohistochemistry for viral proteins demonstrated viral infectivity and replication in hamster gliomas. Flow cytometry revealed increased T cell infiltration in Delta-24-RGD-infected tumors. Delta-24-RGD treatment of tumor-bearing hamsters led to significantly increased survival compared with hamsters treated with PBS. Using this model, we evaluated the effects of corticosteroid-mediated immunosuppression on Delta-24-RGD efficacy. Dexamethasone treatment significantly decreased peripheral blood lymphocytes, decreased tumor-infiltrating lymphocytes, and suppressed the levels of serum anti-adenovirus antibodies. Dexamethasone reduced the number of long-term survivors and decreased the median survival (50 days for Delta-24-RGD + dexamethasone vs undetermined for Delta-24-RGD alone). In summary, we have developed the first adenovirus-permissive, immunocompetent hamster glioma model, addressing a critical need for a model in which to study the role of direct oncolysis in driving immune mediated viral clearance versus driving an antiglioma immune response. Understanding these mechanisms is critical to optimizing the success of oncolytic adenoviral therapy in the clinic.

scholarly journals P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Ana Luisa Palacios-Acedo ◽  
Soraya Mezouar ◽  
Diane Mège ◽  
Lydie Crescence ◽  
Christophe Dubois ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Survival Rates ◽  
Cancer Growth ◽  
Primary Tumors ◽  
Trousseau’S Syndrome ◽  
Pancreatic Cancers ◽  
Cancer Associated Thrombosis

Platelet function can be modified by cancer cells to support tumor growth, causing alterations in the delicate hemostatic equilibrium. Cancer-cell and platelet interactions are one of the main pillars of Trousseau’s syndrome: a paraneoplastic syndrome with recurring and migrating episodes of thrombophlebitis. Altogether, this leads to a four-fold risk of thrombotic events in cancer patients, which in turn, portend a poor prognosis. We previously demonstrated that anti-P2RY12 drugs inhibit cancer-associated-thrombosis and formation of tumor metastasis in pancreatic cancer models. Here, we aimed to (1) compare the effects of aspirin and clopidogrel on pancreatic cancer prevention, (2) characterize the effects of clopidogrel (platelet P2RY12 inhibitor) on cancer-associated thrombosis and cancer growth in vivo, (3) determine the effect of P2RY12 across different digestive-tract cancers in vitro, and (4) analyze the expression pattern of P2RY12 in two different cancer types affecting the digestive system. Clopidogrel treatment resulted in better survival rates with smaller primary tumors and less metastasis than aspirin treatment. Clopidogrel was also more effective than aspirin at dissolving spontaneous endogenous thrombi in our orthotopic advanced cancer mouse model. P2RY12 expression gives pancreatic adenocarcinomas proliferative advantages. In conclusion, we propose the hypothesis that clopidogrel should be further studied to target and prevent Trousseau’s syndrome; as well as diminish cancer growth and spread. However, more studies are required to determine the implicated pathways and effects of these drugs on cancer development.

scholarly journals P01.14 Excessive biological ageing of circulating neutrophils in cancer promotes tumor progression

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A15.1-A15
Author(s):  
CA Reichel ◽  
L Mittmann ◽  
J Schaubächer ◽  
R Hennel ◽  
G Zuchtriegel ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Cell Line ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Biological Ageing ◽  
Functional Changes ◽  
Age Related

BackgroundBeyond their well-established role in host defense, neutrophils are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, ageing of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their anti-infectious properties. The role of neutrophil ageing in cancer is still unknown.Material and MethodsEmploying syngeneic mouse models of head and neck squamous cell carcinoma (cell line SCC VII) and breast cancer (cell line 4T1), cytokine expression (by multiplex ELISA), neutrophil trafficking (by multi-channel in vivo microscopy and flow cytometry), and neutrophil function (in vitro assays) were analyzed.ResultsHere, we show that signals released during early tumor growth promote excessive biological ageing of circulating neutrophils as indicated by age-related changes in their molecular repertoire. These events facilitate the accumulation of these highly reactive immune cells in malignant lesions and endow them with potent pro-tumorigenic functions. In particular, excessively aged neutrophils release neutrophil elastase which, in turn, stimulates the proliferation of cancer cells. Counteracting accelerated biological ageing of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur experimental data uncover a potent self-sustaining mechanism of malignant tumors in fostering pro-tumorigenic phenotypic and functional changes in circulating neutrophils, thus supporting tumor progression. Interference with this aberrant process might provide a novel, already pharmacologically targetable strategy for cancer therapy. This study was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich (SFB) 914.Disclosure InformationC.A. Reichel: None. L. Mittmann: None. J. Schaubächer: None. R. Hennel: None. G. Zuchtriegel: None. M. Canis: None. O. Gires: None. F. Krombach: None. L. Holdt: None. S. Brandau: None. T. Vogl: None. K. Lauber: None. B. Uhl: None.

scholarly journals MicroRNA-384 inhibits nasopharyngeal carcinoma growth and metastasis via binding to Smad5 and suppressing the Wnt/β-catenin axis

2021 ◽  
Author(s):  
Xinyu Zeng ◽  
Huiqun Liao ◽  
Fusen Wang
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Growth ◽  
Survival Rates ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Cell Behaviors ◽  
Online System ◽  
Smad5 Mrna ◽  
Cancer Tissues

AbstractNasopharyngeal carcinoma (NPC) is a major otorhinolaryngological disease with limited effective therapeutic options. This work focused on the function of microRNA-384 (miR-384) on the NPC pathogenesis and the molecules involved. miR-384 expression in cancer tissues and cells was detected. Gain- and loss-of-functions of miR-384 were performed to identify its role in NPC progression. The target mRNA of miR-384 was predicted on an online system and validated through a luciferase reporter assay. The activity of Wnt/β-catenin signaling was detected. Consequently, miR-384 was found to be poorly expressed in NPC tissues and cell lines and was linked to unfavorable survival rates in patients. Overexpression of miR-384 in 6-10B cells suppressed growth, migration, invasion and resistance to apoptosis of cells, but inverse trends were presented in C6661 cells where miR-384 was downregulated. miR-384 targeted Smad5 mRNA. Upregulation of Smad5 counteracted the roles of miR-384 mimic in cells. The NPC-inhibiting effects of miR-384 mimic were also blocked by Wnt/β-catenin activation. To conclude, miR-384 targets Smad5 and inactivates the Wnt/β-catenin pathway, which exerts a suppressing role in NPC cell behaviors as well as tumor growth in vivo. The findings may offer novel thoughts into NPC therapy.

scholarly journals Knockout of High-Mobility Group Box 1 in B16F10 Melanoma Cells Induced Host Immunity-Mediated Suppression of In Vivo Tumor Growth

2021 ◽  
Author(s):  
Kanako Yokomizo ◽  
Kayoko Waki ◽  
Miyako Ozawa ◽  
Keiko Yamamoto ◽  
Sachiko Ogasawara ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
High Mobility

Abstract High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

scholarly journals Crucial Role of the YAP/TEAD Axis in Osteosarcoma Tumor Growth: Effects of YAP Inhibitors Verteporfin and CA3 on Tumor Growth in vivo

2020 ◽  
Author(s):  
Sarah Morice ◽  
Mathilde Mullard ◽  
Regis Brion ◽  
Maryne Dupuy ◽  
Sarah Renault ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Survival Rates ◽  
Osteosarcoma Cell ◽  
Primary Tumor Growth ◽  
Cellular Analysis ◽  
Kaplan Meier

Abstract BackgroundOsteosarcoma is the first primary bone tumor in children and adolescents. Despite progress in the understanding of the biology of these tumors, survival rates have progressed very little in recent decades. In this context, although some studies suggested that disruption of the Hippo signaling pathway is associated with osteosarcoma progression, the molecular mechanisms by which YAP regulates primary tumor growth is not fully clarified. In addition, the validation of YAP as a therapeutic target through the use of inhibitors in a preclinical model must be demonstrated.MethodsThe identification of a YAP signature was carried out by RNAseq analysis from a cohort of patients. Survival rates were assessed by Kaplan-Meier assays. The role of TEAD in the control of osteosarcoma cell proliferation by YAP has been realized by various molecular and cellular biology approaches (RNAseq, PLA, immunoprecipitation, promoter/specific gene, proliferation, cell cycle assays) using overexpression of mutated forms of YAP able or unable to interact with TEAD. The role of TEAD in YAP regulation of primary tumor growth, and the effects of YAP inhibitors in vivo were realized using an orthotopic model of osteosarcoma. ResultsRNA-seq analysis and Kaplan-Meier assays identified a YAP signature in osteosarcoma patients and a correlation with patients outcome. Molecular and cellular analysis using overexpression of mutated forms of YAP able or unable to interact with TEAD, indicate that TEAD is crucial for YAP-driven cell proliferation and in vivo tumor growth. In addition, in vivo experiments show that two YAP/TEAD inhibitors, verteporfin and CA3, reduce primary tumor growth. In this context, in vitro experiments demonstrate that these inhibitors decrease YAP expression, YAP/TEAD transcriptional activity and cell viability mainly by their ability to induce cell apoptosis.ConclusionWe thus demonstrate that the YAP/TEAD signaling axis is a central actor in mediating primary tumor growth of osteosarcoma, and that the use of YAP inhibitors may be a promising therapeutic strategy against osteosarcoma tumor growth.

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