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Drug screening immune response cancer

Eric Shifrut, Julia Carnevale, Victoria Tobin, Theodore L Roth, Jonathan M Woo, Christina T Bui, P Jonathan Li, Morgan E Diolaiti, Alan Ashworth, Alexander Marson
Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, single guide RNA (sgRNA) lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells...
November 13, 2018: Cell
Olha Nazarko, Amanuel Kibrom, Jana Winkler, Katherine Leon, Hannah Stoveken, Gabriel Salzman, Katarzyna Merdas, Yue Lu, Pradnya Narkhede, Gregory Tall, Simone Prömel, Demet Araç
Adhesion G-protein-coupled receptors (aGPCRs) play critical roles in diverse cellular processes in neurobiology, development, immunity, and numerous diseases. The lack of molecular understanding of their activation mechanisms, especially with regard to the transmembrane domains, hampers further studies to facilitate aGPCR-targeted drug development. Latrophilin-1/ADGRL1 is a model aGPCR that regulates synapse formation and embryogenesis, and its mutations are associated with cancer and attention-deficit/hyperactivity disorder...
May 25, 2018: iScience
Wan He, Xiangmei Zhang, Wenwen Li, Cheng Kong, Yuanyang Wang, Lianyu Zhu, Ruilian Xu, Guofang Deng, Peize Zhang
Background: PD-1 checkpoint inhibitors have shown a robust tumor response in the treatment of various cancers. Pembrolizumab is an anti-PD-1 checkpoint antibody approved for the treatment of unresectable or metastatic melanoma in more than 40 countries. Although autoimmune pneumonitis is considered a common immune-related adverse event of PD-1 inhibitors, only limited studies have assessed the development of opportunistic infections such as pulmonary tuberculosis (TB). Case presentation: A patient with metastatic melanoma whose pulmonary TB was activated after administration of pembrolizumab for melanoma is reported...
2018: OncoTargets and Therapy
Henry H Chung, Sean D Bellefeuille, Hayley N Miller, Thomas R Gaborski
Cell migration is essential to many life processes, including immune response, tissue repair, and cancer progression. A reliable quantitative characterization of the cell migration can therefore aid in the high throughput screening of drug efficacy in wound healing and cancer treatments. In this work, we report what we believe is the first use of SiR-Hoechst for extended live tracking and automated analysis of cell migration and wound healing. We showed through rigorous statistical comparisons that this far-red label does not affect migratory behavior...
November 3, 2018: Experimental Cell Research
E Albini, A Coletti, F Greco, M T Pallotta, G Mondanelli, M Gargaro, M L Belladonna, C Volpi, R Bianchi, U Grohmann, A Macchiarulo, C Orabona
Indoleamine 2,3 dioxygenase 1 (IDO1) is a metabolic enzyme that catalyzes the conversion of the essential amino acid tryptophan (Trp) into a series of immunoactive catabolites, collectively known as kynurenines. Through the depletion of Trp and the generation of kynurenines, IDO1 represents a key regulator of the immune responses involved in physiologic homeostasis as well as in neoplastic and autoimmune pathologies. The IDO1 enzyme has been described as an important immune checkpoint to be targeted by catalytic inhibitors in the treatment of cancer...
November 1, 2018: Biochemical Pharmacology
Christopher B Rodell, Sean P Arlauckas, Michael F Cuccarese, Christopher S Garris, Ran Li, Maaz S Ahmed, Rainer H Kohler, Mikael J Pittet, Ralph Weissleder
Tumour-associated macrophages (TAMs) are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet macrophages are highly plastic and can also acquire an anti-tumourigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors (TLRs) TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNPs) lead to efficient drug delivery to TAMs in vivo...
2018: Nature Biomedical Engineering
Jane Harper, Katherine J Adams, Giovanna Bossi, Debbie E Wright, Andrea R Stacey, Nicole Bedke, Ruth Martinez-Hague, Dan Blat, Laure Humbert, Hazel Buchanan, Gabrielle S Le Provost, Zoe Donnellan, Ricardo J Carreira, Samantha J Paston, Luise U Weigand, Martina Canestraro, Joseph P Sanderson, Sophie Botta Gordon-Smith, Kate L Lowe, Karolina A Rygiel, Alex S Powlesland, Annelise Vuidepot, Namir J Hassan, Brian J Cameron, Bent K Jakobsen, Joseph Dukes
Robust preclinical testing is essential to predict clinical safety and efficacy and provide data to determine safe dose for first-in-man studies. There are a growing number of examples where the preclinical development of drugs failed to adequately predict clinical adverse events in part due to their assessment with inappropriate preclinical models. Preclinical investigations of T cell receptor (TCR)-based immunotherapies prove particularly challenging as these biologics are human-specific and thus the conventional testing in animal models is inadequate...
2018: PloS One
Lesley Mathews Griner, Kalyani Gampa, Toan Do, Huyen Nguyen, David Farley, Christopher J Hogan, Douglas S Auld, Serena J Silver
Cancer cells have routinely been cultured in two dimensions (2D) on a plastic surface. This technique, however, lacks the true environment a tumor mass is exposed to in vivo. Solid tumors grow not as a sheet attached to plastic, but instead as a collection of clonal cells in a three-dimensional (3D) space interacting with their neighbors, and with distinct spatial properties such as the disruption of normal cellular polarity. These interactions cause 3D-cultured cells to acquire morphological and cellular characteristics which are more relevant to in vivo tumors...
September 5, 2018: Journal of Visualized Experiments: JoVE
Adrien Costantini, Catherine Julie, Coraline Dumenil, Zofia Hélias-Rodzewicz, Julie Tisserand, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur
Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA...
2018: Oncoimmunology
Simon Hayek, Nassima Bekaddour, Laurie Besson, Rodolphe Alves de Sousa, Nicolas Pietrancosta, Sébastien Viel, Nikaia Smith, Yves Jacob, Sébastien Nisole, Rupasri Mandal, David S Wishart, Thierry Walzer, Jean-Philippe Herbeuval, Pierre-Olivier Vidalain
Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings...
September 5, 2018: SLAS Discovery
Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf Huang
In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death...
August 28, 2018: ACS Nano
Wenxia Xu, Qi Wei, Mengjiao Han, Bingluo Zhou, Hanying Wang, Jianbing Zhang, Qiang Wang, Jie Sun, Lifeng Feng, Shouyu Wang, Yang Ye, Xian Wang, Jianwei Zhou, Hongchuan Jin
Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells...
2018: International Journal of Biological Sciences
Serena Varesano, Maria Raffaella Zocchi, Alessandro Poggi
New successful anti-cancer strategies are based on the stimulation of immune reaction against tumors: however, preclinical testing of such treatments is still a challenge. To improve the screening of anti-cancer drugs, three-dimensional (3D) culture systems, including spheroids, have been validated as preclinical models. We propose the spheroid 3D system to test anti-tumor drug-induced immune responses. We show that colorectal carcinoma (CRC) spheroids, generated with the epithelial growth factor (EGF), can be co-cultured with Vδ2 T cells to evaluate the anti-tumor activity of these effector lymphocytes...
2018: Frontiers in Immunology
Sarah Mancone, Thomas Lycan, Tamjeed Ahmed, Umit Topaloglu, Andrew Dothard, William J Petty, Roy E Strowd
BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising class of anticancer drugs associated with immune-related adverse events (IRAEs). In registration studies of selected cancer populations, neurologic IRAEs were rare. Post-marketing experience describing their prevalence in clinical practice continues to be reported. METHODS: A retrospective cohort of patients treated at our institution with ICIs from 2005 to 2017 was identified. Patients with new neurologic ICD codes documented during or after ICI treatment were enrolled...
May 14, 2018: Journal of Neurology
Elena I Fedoros, Alexey A Orlov, Alexander Zherebker, Ekaterina A Gubareva, Mikhail A Maydin, Andrey I Konstantinov, Konstantin A Krasnov, Ruben N Karapetian, Ekaterina I Izotova, Sergey E Pigarev, Andrey V Panchenko, Margarita L Tyndyk, Dmitry I Osolodkin, Evgeny N Nikolaev, Irina V Perminova, Vladimir N Anisimov
Identification of molecular targets and mechanism of action is always a challenge, in particular - for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines in vitro screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in silico in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties...
April 6, 2018: Oncotarget
Nese Unver, Florencia McAllister
IL-6 is a critical cytokine in acute phase response and involved in the pathogenesis of several chronic inflammatory diseases including cancer. Studies have highlighted that levels of IL-6 and its family members can be useful for diagnosis, prognosis of relapse-free survival and recurrence. IL-6 family cytokines have been identified as cancer biomarkers through screening of inflammatory mediators in different fluids including saliva, serum, and bronchoalveolar lavage fluid (BALF). IL-6 can be modulated by chemopreventive drugs, small molecules, monoclonal antibodies and immune checkpoint inhibitors...
June 2018: Cytokine & Growth Factor Reviews
Fatma B Rashidi, Alanod D AlQhatani, Sara S Bashraheel, Shabnam Shaabani, Matthew R Groves, Alexander Dömling, Sayed K Goda
Repeated cycles of antibody-directed enzyme pro-drug therapy (ADEPT) and the use of glucarpidase in the detoxification of cytotoxic methotrexate (MTX) are highly desirable during cancer therapy but are hampered by the induced human antibody response to glucarpidase. Novel variants of glucarpidase (formal name: carboxypeptidase G2, CPG2) with epitopes not recognized by the immune system are likely to allow repeated cycles of ADEPT for effective cancer therapy. Towards this aim, over two thousand soil samples were collected and screened for folate hydrolyzing bacteria using folate as the sole carbon source...
2018: PloS One
Laura L Eggink, Katherine F Roby, Robert Cote, J Kenneth Hoober
BACKGROUND: Receptors specific for the sugar N-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has been proposed to play an important role in maturation of dendritic cells and initiation of an immune response...
April 17, 2018: Journal for Immunotherapy of Cancer
Santiago Nahuel Villegas, Rita Gombos, Lucia García-López, Irene Gutiérrez-Pérez, Jesús García-Castillo, Diana Marcela Vallejo, Vanina Gabriela Da Ros, Esther Ballesta-Illán, József Mihály, Maria Dominguez
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis...
March 6, 2018: Cell Reports
Keith E Steele, Tze Heng Tan, René Korn, Karma Dacosta, Charles Brown, Michael Kuziora, Johannes Zimmermann, Brian Laffin, Moritz Widmaier, Lorenz Rognoni, Ruben Cardenes, Katrin Schneider, Anmarie Boutrin, Philip Martin, Jiping Zha, Tobias Wiestler
BACKGROUND: Immuno-oncology and cancer immunotherapies are areas of intense research. The numbers and locations of CD8+ tumor-infiltrating lymphocytes (TILs) are important measures of the immune response to cancer with prognostic, pharmacodynamic, and predictive potential. We describe the development, validation, and application of advanced image analysis methods to characterize multiple immunohistochemistry-derived CD8 parameters in clinical and nonclinical tumor tissues. METHODS: Commercial resection tumors from nine cancer types, and paired screening/on-drug biopsies of non-small-cell lung carcinoma (NSCLC) patients enrolled in a phase 1/2 clinical trial investigating the PD-L1 antibody therapy durvalumab (NCT01693562), were immunostained for CD8...
March 6, 2018: Journal for Immunotherapy of Cancer
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