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E Vermeersch, S Liénart, A Collignon, S Lucas, A Gallimore, C Gysemans, D Unutmaz, K Vanhoorelbeke, S F De Meyer, W Maes, H Deckmyn
GARP is a transmembrane protein that presents latent TGF-β1 on the surface of regulatory T cells (Tregs). Neutralizing anti-GARP monoclonal antibodies that prevent the release of active TGF-β1, inhibit the immunosuppressive activity of human Tregs in vivo. In this study, we investigated the contribution of GARP on mouse Tregs to immunosuppression in experimental tumors. Unexpectedly, Foxp3 conditional garp knockout (KO) mice challenged orthotopically with GL261 tumor cells or subcutaneously with MC38 colon carcinoma cells did not show prolonged survival or delayed tumor growth...
July 30, 2018: Cellular Immunology
Jibin Li, Jian Xu, Xiaofei Yan, Keer Jin, Wenya Li, Rui Zhang
BACKGROUND Limited efficacy of immune checkpoint blockades was observed in clinical trials in colorectal (CRC) patients, especially in the microsatellite-stable patients. Interleukin-6 (IL-6) is critical in modeling immune responses in cancers. However, the effects of targeting IL-6 in combination with immune checkpoint blockades is unknown in CRC. MATERIAL AND METHODS In the present study, we investigated the profile of IL-6 expression in tumor tissues of CRC patient and we established CRC mouse models with various IL-6 expression levels using CT26 cells and MC38 cells...
August 8, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Stacy J Kowalsky, Zuqiang Liu, Mathilde Feist, Sara E Berkey, Congrong Ma, Roshni Ravindranathan, Enyong Dai, Edward J Roy, Zong Sheng Guo, David L Bartlett
Oncolytic immunotherapy is a promising novel therapeutic for cancer, and further preclinical studies may maximize its therapeutic efficacy. In this study, we construct a novel oncolytic vaccinia virus (VV) expressing a superagoinst IL-15, a fusion protein of IL-15 and IL-15Ralpha. This virus, named vvDD-IL15-Rα, possesses similar replication efficiency as the parental virus vvDD yet leads to significantly more regression of the disease and extends the survival of mice bearing MC38 colon or ID8 ovarian cancer...
July 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Genyuan Zhu, Satoshi Nemoto, Adam W Mailloux, Patricio Perez-Villarroel, Ryosuke Nakagawa, Rana Falahat, Anders E Berglund, James J Mulé
Tertiary lymphoid structures (TLSs) associate with better prognosis in certain cancer types, but their underlying formation and immunological benefit remain to be determined. We established a mouse model of TLSs to study their contribution to antitumor immunity. Because the stroma in lymph nodes (sLN) participates in architectural support, lymphogenesis, and lymphocyte recruitment, we hypothesized that TLSs can be created by sLN. We selected a sLN line with fibroblast morphology that expressed sLN surface markers and lymphoid chemokines...
2018: Frontiers in Immunology
Xiang Hu, Ya-Qi Li, Qing-Guo Li, Yan-Lei Ma, Jun-Jie Peng, San-Jun Cai
BACKGROUND: OGN could modify tissue inflammation and immune response via local and circulating innate immune cells, which was suggestive of a reciprocal relationship between OGN and T cell infiltration in cancer. Hence, we aim to measure the OGN expression patterns and immune cells response in colorectal cancer(CRC). METHODS: This study enrolled three independent sets of patients from TCGA and the Fudan University Shanghai Cancer Center(FUSCC). The effect of OGN on T cell infiltration and the mechanism were examined in vitro and in vivo...
July 20, 2018: EBioMedicine
Qinrui Han, Ye Ma, Hao Wang, Yu Dai, Chunhui Chen, Yawei Liu, Linlin Jing, Xuegang Sun
BACKGROUND: Necroptotic susceptibility is probably an intrinsic weakness of cancer. Here, we report that resibufogenin, a member of bufadienolide family, suppresses the growth and metastasis of colorectal cancer (CRC) through induction of necroptosis in vivo. METHODS: SW480 cells with stably expressing enhanced green fluorescence protein were xenografted to BALB/c-nu mice to observe the growth of tumors. Liver metastasis was observed by injection of MC38 cells beneath the splenic capsule of mice...
July 20, 2018: Journal of Translational Medicine
Joanna Rossowska, Natalia Anger, Agnieszka Szczygieł, Jagoda Mierzejewska, Elżbieta Pajtasz-Piasecka
BACKGROUND: The excessive amounts of immunosuppressive factors present in a tumor microenvironment (TME) reduce the effectiveness of cancer vaccines. The main objective of our research was to improve the effectiveness of dendritic cell (DC)-based immunotherapy or chemoimmunotherapy composed of cyclophosphamide (CY) and DCs by application of lentivectors encoding shRNA specific to IL-10 (shIL10 LVs) in murine colon carcinoma MC38 model. METHODS: The efficacy of shIL10 LVs in silencing of IL-10 expression was measured both in vitro and in vivo using Real-Time PCR and ELISA assays...
June 28, 2018: Journal of Experimental & Clinical Cancer Research: CR
Fangxia Guan, Tahmineh Tabrizian, Ardijana Novaj, Masako Nakanishi, Daniel W Rosenberg, Derek M Huffman
Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer...
2018: Frontiers in Nutrition
Heidi Harjunpää, Stephen J Blake, Elizabeth Ahern, Stacey Allen, Jing Liu, Juming Yan, Viviana Lutzky, Kazuyoshi Takeda, Amy Roman Aguilera, Camille Guillerey, Deepak Mittal, Xian Yang Li, William C Dougall, Mark J Smyth, Michele W L Teng
Multiple non-redundant immunosuppressive pathways co-exist in the tumor microenvironment and their co-targeting can increase clinical responses. Indeed, concurrent blockade of CTLA-4 and PD-1 in patients with advanced melanoma increased clinical responses over monotherapy alone although the frequency and severity of immune related adverse events (irAEs) also increased. Nevertheless, a substantial number of patients still display an innate resistance phenotype and are unresponsive to current approved immunotherapies even when utilized in combination...
2018: Oncoimmunology
Xinqiang Hong, Tiangeng Dong, Tuo Yi, Jianwei Hu, Zhen Zhang, Shengli Lin, Weixin Niu
Objective: The aim of the present study was to investigate the effects of 5-fluorouracil (5-Fu) and oxaliplatin on the function and activation pathways of mouse dendritic cells (DCs), and to clarify whether 5-Fu/oxaliplatin combined with the CD1d-MC38/α-galactosylceramide (α-GC) tumor vaccine exhibits synergistic effects on the treatment of colon cancer in mice. Methods: The combination of the Toll like receptor (TLR) ligands and/or 5-Fu/oxaliplatin was added into myeloid-derived DCs in vitro culture...
April 2018: Chinese Journal of Cancer Research, Chung-kuo Yen Cheng Yen Chiu
Zhijie Lin, Sen Han, Xingxing Qian, Chunxia Hu, Weiming Xiao, Li Qian, Yu Zhang, Yanbing Ding, Xiaoqin Jia, Guoqiang Zhu, Weijuan Gong
Regulatory T cells play critical roles in self-tolerance and tumor evasion. CD4+ NKG2D+ cells with regulatory activity are present in patients with NKG2DL+ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing CD4+ NKG2D+ T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.1- CD4+ NKG2D+ T cells have regulatory activity in pCD86-Rae-1ε transgenic mice...
July 2018: Cancer Immunology, Immunotherapy: CII
N Moore, D Doty, M Zielstorff, I Kariv, L Y Moy, A Gimbel, J R Chevillet, N Lowry, J Santos, V Mott, L Kratchman, T Lau, G Addona, H Chen, J T Borenstein
Recapitulation of the tumor microenvironment is critical for probing mechanisms involved in cancer, and for evaluating the tumor-killing potential of chemotherapeutic agents, targeted therapies and immunotherapies. Microfluidic devices have emerged as valuable tools for both mechanistic studies and for preclinical evaluation of therapeutic agents, due to their ability to precisely control drug concentrations and gradients of oxygen and other species in a scalable and potentially high throughput manner. Most existing in vitro microfluidic cancer models are comprised of cultured cancer cells embedded in a physiologically relevant matrix, collocated with vascular-like structures...
June 26, 2018: Lab on a Chip
Rui Kuai, Wenmin Yuan, Sejin Son, Jutaek Nam, Yao Xu, Yuchen Fan, Anna Schwendeman, James J Moon
Although immune checkpoint blockade has shown initial success for various cancers, only a small subset of patients benefits from this therapy. Some chemotherapeutic drugs have been reported to induce antitumor T cell responses, prompting a number of clinical trials on combination chemoimmunotherapy. However, how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy remains unclear. We show that high-density lipoprotein-mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models...
April 2018: Science Advances
Douglas W Brown, Arya J Bahrami, David A Canton, Anandaroop Mukhopadhyay, Jean S Campbell, Robert H Pierce, Richard J Connolly
Intratumoral electroporation of plasmid DNA encoding the proinflammatory cytokine interleukin 12 promotes innate and adaptive immune responses correlating with anti-tumor effects. Clinical electroporation conditions are fixed parameters optimized in preclinical tumors, which consist of cells implanted into skin. These conditions have little translatability to clinically relevant tumors, as implanted models cannot capture the heterogeneity encountered in genetically engineered mouse models or clinical tumors...
August 2018: Bioelectrochemistry
Junya Kitadani, Toshiyasu Ojima, Hiromitsu Iwamoto, Hirotaka Tabata, Mikihito Nakamori, Masaki Nakamura, Keiji Hayata, Masahiro Katsuda, Masayasu Miyajima, Hiroki Yamaue
Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model...
March 15, 2018: Scientific Reports
Jessica Wagner, C Leah Kline, Lanlan Zhou, Kerry S Campbell, Alexander W MacFarlane, Anthony J Olszanski, Kathy Q Cai, Harvey H Hensley, Eric A Ross, Marie D Ralff, Andrew Zloza, Charles B Chesson, Jenna H Newman, Howard Kaufman, Joseph Bertino, Mark Stein, Wafik S El-Deiry
ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion...
June 1, 2018: Journal of Clinical Investigation
Zhi-Bin Zhao, Jie Long, Yang-Yang Zhao, Jing-Bo Yang, Wei Jiang, Qing-Zhi Liu, Kai Yan, Liang Li, Yu-Cai Wang, Zhe-Xiong Lian
Sorafenib is a kinase inhibitor approved for the treatment of primary kidney cancer, advanced primary liver cancer, and radioactive iodine resistant advanced thyroid carcinoma. However, sorafenib usually causes serious side effects, which limit its antitumor effect. Nanoparticle based drug delivery systems have been widely used to enhance the therapeutic effects and reduce the side effects of this drug by the enhanced permeability and retention (EPR) effect. Herein, to improve the therapeutic effect of sorafenib, we developed poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA) based nanoparticles by a dialysis method for sorafenib encapsulation...
March 26, 2018: Biomaterials Science
Elizabeth A Kuczynski, Janna Krueger, Annabelle Chow, Ping Xu, Shan Man, Yogi Sundaravadanam, Jessica K Miller, Paul M Krzyzanowski, Robert S Kerbel
A recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade...
April 2018: Molecular Cancer Therapeutics
Haizhou Liu, Hui Liu, Zhiyi Zhou, Robert A Parise, Edward Chu, John C Schmitz
BACKGROUND: 5-Fluorouracil (5-FU) remains the most widely used agent to treat colorectal cancer (CRC). However, its clinical efficacy is currently limited by the development of drug resistance. Traditional Chinese Herbal Medicine (TCM) has been shown to enhance the efficacy of standard anticancer agents. However, there are only a limited number of well-controlled preclinical and clinical studies documenting the potential benefit of TCM. Herein, we screened a series of TCM formulas in in vitro and in vivo animal models to identify biologically active formulas that were effective against CRC...
February 20, 2018: Cell Communication and Signaling: CCS
Changwei Dou, Zhikui Liu, Kangsheng Tu, Hongbin Zhang, Chen Chen, Usman Yaqoob, Yuanguo Wang, Jialing Wen, Jan van Deursen, Delphine Sicard, Daniel Tschumperlin, Hongzhi Zou, Wei-Chien Huang, Raul Urrutia, Vijay H Shah, Ningling Kang
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) contribute to desmoplasia and stiffness of liver metastases by differentiating into matrix-producing myofibroblasts. We investigated whether stiffness due to the presence of tumors increases activation of HSCs into myofibroblasts and their tumor-promoting effects, as well as the role of E1A binding protein p300, a histone acetyltransferase that regulates transcription, in these processes. METHODS: HSCs were isolated from liver tissues of patients, mice in which the p300 gene was flanked by 2 loxP sites (p300F/F mice), and p300+/+ mice (controls)...
June 2018: Gastroenterology
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