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A Blanas, L A M Cornelissen, M Kotsias, J C van der Horst, H J van de Vrugt, H Kalay, D I R Spencer, R P Kozak, S J van Vliet
Aberrant fucosylation in cancer cells is considered as a signature of malignant cell transformation and it is associated with tumor progression, metastasis and resistance to chemotherapy. Specifically, in colorectal cancer cells, increased levels of the fucosylated Lewisx antigen are attributed to the deregulated expression of pertinent fucosyltransferases, like fucosyltransferase 4 (FUT4) and fucosyltransferase 9 (FUT9). However, the lack of experimental models closely mimicking cancer-specific regulation of fucosyltransferase gene expression has, so far, limited our knowledge regarding the substrate specificity of these enzymes and the impact of Lewisx synthesis on the glycome of colorectal cancer cells...
November 22, 2018: Glycobiology
Keaton I Jones, Jiske Tiersma, Arseniy E Yuzhalin, Alex N Gordon-Weeks, Jon Buzzelli, Jae Hong Im, Ruth J Muschel
Emerging evidence suggests a role for radiation in eliciting anti-tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony-stimulating factor 1 (CSF-1). Coincident with the elevation in CSF-1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour-associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype...
November 15, 2018: EMBO Molecular Medicine
Juhyun Oh, Angela Magnuson, Christophe Benoist, Mikael J Pittet, Ralph Weissleder
Cancer incidence increases with age, but paradoxically, cancers have been found to grow more quickly in young mice compared with aged ones. The cause of differential tumor growth has been debated and, over time, attributed to faster tumor cell proliferation, decreased tumor cell apoptosis, and/or increased angiogenesis in young animals. Despite major advances in our understanding of tumor immunity over the past 2 decades, little attention has been paid to comparing immune cell populations in young and aged mice...
November 2, 2018: JCI Insight
Chloé Grasselly, Morgane Denis, Aurore Bourguignon, Nolan Talhi, Doriane Mathe, Anne Tourette, Laurent Serre, Lars Petter Jordheim, Eva Laure Matera, Charles Dumontet
In spite of impressive response rates in multiple cancer types, immune checkpoint inhibitors (ICIs) are active in only a minority of patients. Alternative strategies currently aim to combine immunotherapies with conventional agents such as cytotoxic chemotherapies. Here, we performed a study of PD-1 or PDL-1 blockade in combination with reference chemotherapies in four fully immunocompetent mouse models of cancer. We analyzed both the in vivo antitumor response, and the tumor immune infiltrate 4 days after the first treatment...
2018: Frontiers in Immunology
Long Wang, Yuxi Zhou, Jiemin Yin, Yu Gan, Xin Wang, Daxiang Wen, Angus W Thomson, Xiaoming Hu, Liqun Yang, R Anne Stetler, Peiying Li, Weifeng Yu
Background and Purpose- Adoptive transfer of regulatory T cells (Tregs) protect against stroke; however, Treg-based therapy raises concerns in stroke patients with cancer because of the immunosuppressive function of Tregs. The purpose of this study was to investigate the role of Tregs in cerebral ischemic brain injury with concomitant cancer. Methods- To establish a cancer phenotype, MC38 colon cancer or B16 melanoma cells (5×105 /mice) were injected subcutaneously into C57BL/6J mice 2 to 3 weeks before distal middle cerebral artery occlusion surgery...
November 2018: Stroke; a Journal of Cerebral Circulation
Shu-Han Yu, Janielle P Maynard, Ajay M Vaghasia, Angelo M De Marzo, Charles G Drake, Karen S Sfanos
BACKGROUND: Interleukin-6 (IL-6) is a mediator of inflammation that can facilitate prostate cancer progression. We previously demonstrated that IL-6 is present in the prostate tumor microenvironment and is restricted almost exclusively to the stromal compartment. The present study examined the influence of paracrine IL-6 signaling on prostate tumor growth using allograft models of mouse prostate cancer (TRAMP-C2), colon cancer (MC38), and melanoma (B16) cell lines in wildtype (WT) and IL-6 knockout (IL-6-/- ) mice...
October 21, 2018: Prostate
Benjamin M Larimer, Emily G Bloch, Sarah Nesti, Emily E Austin, Eric Wehrenberg-Klee, Genevieve Boland, Umar Mahmood
PURPOSE: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy. EXPERIMENTAL DESIGN: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Meinolf Thiemann, David M Richards, Karl Heinonen, Michael Kluge, Viola Marschall, Christian Merz, Mauricio Redondo Müller, Tim Schnyder, Julian P Sefrin, Jaromir Sykora, Harald Fricke, Christian Gieffers, Oliver Hill
Tumor necrosis factor receptor superfamily member 7 (TNFRSF7, CD27), expressed primarily by T cells, and its ligand CD27L (TNFSF7, CD70) provide co-stimulatory signals that boost T cell activation, differentiation, and survival. Agonistic stimulation of CD27 is therefore a promising therapeutic concept in immuno-oncology intended to boost and sustain T cell driven anti-tumor responses. Endogenous TNFSF/TNFRSF-based signal transmission is a structurally well-defined event that takes place during cell-to-cell-based contacts...
2018: Frontiers in Oncology
Alfonso R Sanchez-Paulete, Alvaro Teijeira, Jose I Quetglas, Maria E Rodriguez-Ruiz, Alvaro Sanchez-Arraez, Sara Labiano, Inaki Etxeberria, Arantza Azpilikueta, Elixabet Bolaños, Maria Cristina Ballesteros-Briones, Noelia Casares, Sergio A Quezada, Pedro Berraondo, David Sancho, Cristian Smerdou, Ignacio Melero
Multiple lines of evidence indicate a critical role for antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1 respectively constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to tumor cells in culture and when engrafted as subcutaneous mouse tumor models...
October 8, 2018: Cancer Research
Christian Merz, Jaromir Sykora, Viola Marschall, David M Richards, Karl Heinonen, Mauricio Redondo Müller, Meinolf Thiemann, Tim Schnyder, Harald Fricke, Oliver Hill, Christian Gieffers
CD40 ligand (TNFSF5/CD154/CD40L), a member of the tumor necrosis factor (TNF) superfamily is a key regulator of the immune system. The cognate receptor CD40 (TNFRSF5) is expressed broadly on antigen-presenting cells and many tumor types, and has emerged as an attractive target for immunologic cancer treatment. Most of the CD40 targeting drugs in clinical development are antibodies which display some disadvantages: their activity typically depends on Fcγ receptor-mediated crosslinking, and depletion of CD40-expressing immune cells by antibody-dependent cellular cytotoxicity compromises an efficient antitumor response...
November 2018: Journal of Immunotherapy
Heng Sheng Sow, Hreinn Benonisson, Cor Breukel, Remco Visser, Onno J H M Verhagen, Arthur E H Bentlage, Conny Brouwers, Jill W C Claassens, Margot M Linssen, Marcel Camps, Thorbald van Hall, Ferry Ossendorp, Marieke F Fransen, Gestur Vidarsson, J Sjef Verbeek
Immunomodulatory antibodies blocking interactions of co-inhibitory receptors to their ligands such as CTLA-4, PD1 and PD-L1 on immune cells have shown impressive therapeutic efficacy in clinical studies. The therapeutic effect of these antibodies is mainly mediated by re-activating antitumor T cell immune responses. Detailed analysis of anti-CTLA4 antibody therapy revealed that an optimal therapeutic efficacy also requires binding to Fc receptors for IgG, FcγR, mediating depletion of intratumoral regulatory T cells...
September 27, 2018: International Journal of Cancer. Journal International du Cancer
Mengxin Xu, Yuxiang Han, Guizhong Liu, Yang Xu, Dongban Duan, Hui Liu, Felix Du, Peter Luo, Zhibo Liu
Recently, inhibiting the PD-1/PD-L1 checkpoint pathway utilizing anti-PD-1 or anti-PD-L1 antibodies has achieved great clinical success in cancer treatment. However, anti-PD-1 immunotherapy cannot be applied to all cancer patients, no more than 25% showed a positive response. Immunohistochemistry (IHC) is the gold standard to determine the PD-L1 expression level in malignant lesions, but a noninvasive imaging-meditated strategy is urgently required for clinical diagnosis to cover the shortcomings of invasive techniques...
September 4, 2018: Molecular Pharmaceutics
Yongkui Li, Jie Shi, Shanshan Qi, Jian Zhang, Dong Peng, Zhenzhen Chen, Guobin Wang, Zheng Wang, Lin Wang
BACKGROUND: Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear. METHODS: We analyzed IL-33 gene expression in human colorectal cancer (CRC) tissues and carried out gene enrichment analysis with TCGA Data Portal. We studied CRC proliferation in vivo by inoculating MC38 tumors in IL-33 transgenic mice...
August 17, 2018: Journal of Experimental & Clinical Cancer Research: CR
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...
October 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...
October 3, 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...
August 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
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