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Oncoimmunology

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https://www.readbyqxmd.com/read/28680763/the-influence-of-stromal-cells-and-tumor-microenvironment-derived-cytokines-and-chemokines-on-cd3-cd8-tumor-infiltrating-lymphocyte-subpopulations
#1
Stefan Koeck, Johan Kern, Marit Zwierzina, Gabriele Gamerith, Edith Lorenz, Sieghart Sopper, Heinz Zwierzina, Arno Amann
The tumor microenvironment has been identified as a major mediator of immunological processes in solid tumors. In particular, tumor-associated fibroblasts are known to interact with tumor infiltrating immune cells. We describe the influence of fibroblasts and tumor-microenvironment-derived cytokines on the infiltration capacity of CD3(+)CD8(+) cytotoxic T lymphocyte subpopulations using a multicellular 3D co-culture system. 3D tumor microtissues were cultivated using a hanging drop system. Human A549 and Calu-6 cancer cell lines were incubated alone or together with the human fibroblast cell line SV80 for 10 d to form microtissues...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680762/tumor-targeted-il-12-combined-with-local-irradiation-leads-to-systemic-tumor-control-via-abscopal-effects-in-vivo
#2
Franziska Eckert, Ivan Jelas, Moritz Oehme, Stephan M Huber, Katja Sonntag, Christian Welker, Stephen D Gillies, Wolfgang Strittmatter, Daniel Zips, Rupert Handgretinger, Karin Schilbach
NHS-IL12 is an immunocytokine, a fusion protein of IL12's functional domains and a necrosis-targeting antibody, which has shown significant effects against human rhabdomyosarcoma xenografts in a humanized tumor model, including terminal growth arrest and differentiation of the tumor cells. Here, we locally irradiated the tumors, increasing necrosis and consequently intratumoral immune cytokine availability, and asked whether this effect may surmount efficacy of single treatment modality. Humanized mice bearing bilateral rhabdomyosarcoma xenografts were evaluated for tumor burden and survival after irradiation, systemic NHS-IL12 therapy or a combination of both...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680761/the-splenic-marginal-zone-shapes-the-phenotype-of-leukemia-b-cells-and-facilitates-their-niche-specific-retention-and-survival
#3
Vanessa Stache, Lydia Verlaat, Marcel Gätjen, Kristina Heinig, Jörg Westermann, Armin Rehm, Uta E Höpken
Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5(-/-)Eµ-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5(-/-)Eµ-Tcl1 cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680760/tbet-and-il-36%C3%AE-cooperate-in-therapeutic-dc-mediated-promotion-of-ectopic-lymphoid-organogenesis-in-the-tumor-microenvironment
#4
Aliyah M Weinstein, Lu Chen, Emily A Brzana, Prashanti R Patil, Jennifer L Taylor, Kellsye L Fabian, Callen T Wallace, Sabrina D Jones, Simon C Watkins, Binfeng Lu, David F Stroncek, Timothy L Denning, Yang-Xin Fu, Peter A Cohen, Walter J Storkus
We have previously reported that direct injection of dendritic cells (DC) engineered to express the Type-1 transactivator Tbet (i.e., DC.Tbet) into murine tumors results in antitumor efficacy in association with the development of structures resembling tertiary lymphoid organs (TLO) in the tumor microenvironment (TME). These TLO contained robust infiltrates of B cells, DC, NK cells, and T cells in proximity to PNAd(+) blood vessels; however, they were considered incomplete, since the recruited B cells failed to organize into classic germinal center-like structures...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680759/parallel-profiling-of-immune-infiltrate-subsets-in-uveal-melanoma-versus-cutaneous-melanoma-unveils-similarities-and-differences-a-pilot-study
#5
Yong Qin, Mariana Petaccia de Macedo, Alexandre Reuben, Marie-Andrée Forget, Cara Haymaker, Chantale Bernatchez, Christine N Spencer, Vancheswaran Gopalakrishnan, Sujan Reddy, Zachary A Cooper, Orenthial J Fulbright, Renjith Ramachandran, Arely Wahl, Esteban Flores, Shawne T Thorsen, Rene J Tavera, Claudius Conrad, Michelle D Williams, Michael T Tetzlaff, Wei-Lien Wang, Dan S Gombos, Bita Esmaeli, Rodabe N Amaria, Patrick Hwu, Jennifer A Wargo, Alexander J Lazar, Sapna P Patel
The low response rates to immunotherapy in uveal melanoma (UM) sharply contrast with reputable response rates in cutaneous melanoma (CM) patients. To characterize the mechanisms responsible for resistance to immunotherapy in UM, we performed immune profiling in tumors from 10 metastatic UM patients and 10 metastatic CM patients by immunohistochemistry (IHC). Although there is no difference in infiltrating CD8(+) T cells between UM and CM, a significant decrease in programmed death-1 (PD-1)-positive lymphocytes was observed and lower levels of programmed death ligand-1 (PD-L1) in UM metastases compared with CM metastases...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680758/immune-classifications-with-cytotoxic-cd8-and-th17-infiltrates-are-predictors-of-clinical-prognosis-in-glioblastoma
#6
Rachid Madkouri, Coureche Guillaume Kaderbhai, Aurélie Bertaut, Caroline Truntzer, Julie Vincent, Marie Hélene Aubriot-Lorton, Walid Farah, Emeric Limagne, Sylvain Ladoire, Romain Boidot, Valentin Derangère, François Ghiringhelli
BACKGROUND: Interest is growing on immune cells involvement in central nervous system tumors such as glioblastoma. Even if a few reports highlighted that immune classifications could have a prognostic value, no paradigm has been clearly yet established on large and homogeneous cohorts. The aim of our study was to analyze the prognostic role of the in situ immune response of cytotoxic T cells (i.e., CD8(+)), Foxp3 cells, Th17 and tumor-associated macrophages in glioblastoma on two independent large and homogeneous cohorts...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680757/downregulation-of-ptp1b-and-tc-ptp-phosphatases-potentiate-dendritic-cell-based-immunotherapy-through-il-12-ifn%C3%AE-signaling
#7
Claudia Penafuerte, Matthew Feldhammer, John R Mills, Valerie Vinette, Kelly A Pike, Anita Hall, Eva Migon, Gerard Karsenty, Jerry Pelletier, George Zogopoulos, Michel L Tremblay
PTP1B and TC-PTP are highly related protein-tyrosine phosphatases (PTPs) that regulate the JAK/STAT signaling cascade essential for cytokine-receptor activation in immune cells. Here, we describe a novel immunotherapy approach whereby monocyte-derived dendritic cell (moDC) function is enhanced by modulating the enzymatic activities of PTP1B and TC-PTP. To downregulate or delete the activity/expression of these PTPs, we generated mice with PTP-specific deletions in the dendritic cell compartment or used PTP1B and TC-PTP specific inhibitor...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680756/amplification-of-n-myc-is-associated-with-a-t-cell-poor-microenvironment-in-metastatic-neuroblastoma-restraining-interferon-pathway-activity-and-chemokine-expression
#8
Julian P Layer, Marie T Kronmüller, Thomas Quast, Debby van den Boorn-Konijnenberg, Maike Effern, Daniel Hinze, Kristina Althoff, Alexander Schramm, Frank Westermann, Martin Peifer, Gunther Hartmann, Thomas Tüting, Waldemar Kolanus, Matthias Fischer, Johannes Schulte, Michael Hölzel
Immune checkpoint inhibitors have significantly improved the treatment of several cancers. T-cell infiltration and the number of neoantigens caused by tumor-specific mutations are correlated to favorable responses in cancers with a high mutation load. Accordingly, checkpoint immunotherapy is thought to be less effective in tumors with low mutation frequencies such as neuroblastoma, a neuroendocrine tumor of early childhood with poor outcome of the high-risk disease group. However, spontaneous regressions and paraneoplastic syndromes seen in neuroblastoma patients suggest substantial immunogenicity...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680755/bispecific-antibody-does-not-induce-t-cell-death-mediated-by-chimeric-antigen-receptor-against-disialoganglioside-gd2
#9
Sayed Shahabuddin Hoseini, Konstantin Dobrenkov, Dmitry Pankov, Xiaoliang L Xu, Nai-Kong V Cheung
Chimeric antigen receptors (CAR) and bispecific antibodies (BsAb) are two powerful immunotherapy approaches for retargeting lymphocytes toward cancer cells. Despite their success in lymphoblastic leukemia, solid tumors have been more recalcitrant. Identifying therapeutic barriers facing CAR-modified (CART) or BsAb-redirected T (BsAb-T) cells should facilitate their clinical translation to solid tumors. Novel lentiviral vectors containing low-affinity or high-affinity 4-1BB second-generation anti-GD2 (disialoganglioside) CARs were built to achieve efficient T cell transduction...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680754/cd39-cd73-upregulation-on-myeloid-derived-suppressor-cells-via-tgf-%C3%AE-mtor-hif-1-signaling-in-patients-with-non-small-cell-lung-cancer
#10
Jieyao Li, Liping Wang, Xinfeng Chen, Lifeng Li, Yu Li, Yu Ping, Lan Huang, Dongli Yue, Zhen Zhang, Fei Wang, Feng Li, Li Yang, Jianmin Huang, Shuangning Yang, Hong Li, Xuan Zhao, Wenjie Dong, Yan Yan, Song Zhao, Bo Huang, Bin Zhang, Yi Zhang
CD39/CD73-adenosine pathway has been recently defined as an important tumor-induced immunosuppressive mechanism. We here documented a fraction of CD11b(+)CD33(+) myeloid-derived suppressor cells (MDSCs) in peripheral blood and tumor tissues from non-small cell lung cancer (NSCLC) patients expressed surface ectonucleotidases CD39 and CD73. Tumor TGF-β stimulated CD39 and CD73 expression, thereby inhibited T cell and NK cell activity, and protected tumor cells from the cytotoxic effect of chemotherapy through ectonucleotidase activity...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680753/efficacy-of-vaccination-with-tumor-exosome-loaded-dendritic-cells-combined-with-cytotoxic-drug-treatment-in-pancreatic-cancer
#11
Li Xiao, Ulrike Erb, Kun Zhao, Thilo Hackert, Margot Zöller
Pancreatic cancer (PaCa) has a dismal prognosis and adjuvant immunotherapy frequently is of low efficacy due to immunosuppressive features of PaCa and PaCa-stroma. We here explored, whether the efficacy of vaccination with tumor-exosome (TEX)-loaded dendritic cells (DC) can be improved by combining with drugs affecting myeloid-derived suppressor cells (MDSC). Experiments were performed with the UNKC6141 PaCa line. UNKC6141 TEX-loaded DC were weekly intravenously injected, mice additionally receiving Gemcitabine (GEM) and/or ATRA and/or Sunitinib (Sun)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680752/oral-il-10-suppresses-colon-carcinogenesis-via-elimination-of-pathogeniccd4-t-cells-and-induction-of-antitumor-cd8-t-cell-activity
#12
Tao Gu, Magdia De Jesus, Heather C Gallagher, Thomas P Burris, Nejat K Egilmez
An oral sustained-release formulation of Interleukin-10 suppressed tumor growth and enhanced survival in the APC(min/+)/Bacteroides fragilis spontaneous colon cancer model. Therapeutic benefit was associated with a 5-fold reduction in CD4(+)RORγt(+)Foxp3(-)IL-17(+) T-helper cell, CD4(+)RORγt(+)Foxp3(+)IL-17(+) pathogenic T-regulatory cell and CD4(+)RORγt(-)Foxp3(+)IL-17(-) conventional T-regulatory cell numbers and a concurrent 2-fold enhancement in CD8(+) T-cell activity in the colon. Selective subset depletion and functional blockade studies demonstrated that at steady-state CD4(+)RORγt(+)IL-17(+) T-cell subsets and CD4(+)Foxp3(+) cTreg supported tumorigenesis, whereas CD8(+) cytotoxic T-lymphocytes impeded tumor progression following IL-10 therapy...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680751/tocilizumab-in-patients-with-multisystem-erdheim-chester-disease
#13
Alvise Berti, Giulio Cavalli, Barbara Guglielmi, Riccardo Biavasco, Corrado Campochiaro, Alessandro Tomelleri, Roberto Nicoletti, Andrea Panzacchi, Marina Ferrarini, Lorenzo Dagna
Treatment of Erdheim-Chester disease (ECD), a rare non-Langerhans histiocytosis, relies on interferon-α, chemotherapeutic agents such as purine analogs, cytokine-blocking agents and BRAF inhibitors. Since interleukin (IL)-6 levels are elevated in serum and lesions of ECD patients, we evaluated the therapeutic efficacy and safety of IL-6 blockade with tocilizumab. We conducted an open-label, single-arm, phase II, prospective study of tocilizumab in three patients with multisystem ECD and poor tolerance/contraindications to IFN-α...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680750/il-33-restricts-tumor-growth-and-inhibits-pulmonary-metastasis-in-melanoma-bearing-mice-through-eosinophils
#14
Valeria Lucarini, Giovanna Ziccheddu, Iole Macchia, Valentina La Sorsa, Francesca Peschiaroli, Carla Buccione, Antonella Sistigu, Massimo Sanchez, Sara Andreone, Maria Teresa D'Urso, Massimo Spada, Daniele Macchia, Claudia Afferni, Fabrizio Mattei, Giovanna Schiavoni
The alarmin IL-33 is an IL-1 family member that stimulates pleiotropic immune reactions depending on the target tissue and microenvironmental factors. In this study, we have investigated the role of IL-33/ST2 axis in antitumor response to melanoma. Injection of IL-33 in mice-bearing subcutaneous B16.F10 melanoma resulted in significant tumor growth delay. This effect was associated with intratumoral accumulation of CD8(+) T cells and eosinophils, decrease of immunosuppressive myeloid cells, and a mixed Th1/Th2 cytokine expression pattern with local and systemic activation of CD8(+) T and NK cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680749/tumor-priming-converts-nk-cells-to-memory-like-nk-cells
#15
Marina Pal, Lisa Schwab, Anastasiya Yermakova, Emily M Mace, Rainer Claus, Ann-Christin Krahl, Jeanette Woiterski, Udo F Hartwig, Jordan S Orange, Rupert Handgretinger, Maya C André
Fascinating earlier evidence suggests an intrinsic capacity of human natural killer (NK) cells to acquire adaptive immune features in the context of cytomegalovirus (CMV) infection or pro-inflammatory cytokine stimulation. Since the role of memory NK cells in cancer has so far remained elusive and adoptive NK cell transfer in relapsing pediatric acute B cell precursor leukemia (BCP-ALL) patients awaits improvement, we asked the question whether tumor-priming could promote the generation of memory NK cells with enhanced graft-vs...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680748/mycn-is-an-immunosuppressive-oncogene-dampening-the-expression-of-ligands-for-nk-cell-activating-receptors-in-human-high-risk-neuroblastoma
#16
Elisa Brandetti, Irene Veneziani, Ombretta Melaiu, Annalisa Pezzolo, Aurora Castellano, Renata Boldrini, Elisa Ferretti, Doriana Fruci, Lorenzo Moretta, Vito Pistoia, Franco Locatelli, Loredana Cifaldi
Neuroblastoma (NB) is the most common extracranial solid tumor occurring in childhood. Amplification of the MYCN oncogene is associated with poor prognosis. Downregulation on NB cells of ligands recognized by Natural Killer (NK) cell-activating receptors, involved in tumor cell recognition and lysis, may contribute to tumor progression and relapse. Here, we demonstrate that in human NB cell lines MYCN expression inversely correlates with that of ligands recognized by NKG2D and DNAM1 activating receptors in human NB cell lines...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680747/arginase-inhibition-suppresses-lung-metastasis-in-the-4t1-breast-cancer-model-independently-of-the-immunomodulatory-and-anti-metastatic-effects-of-vegfr-2-blockade
#17
Chiara Secondini, Oriana Coquoz, Lorenzo Spagnuolo, Thibaud Spinetti, Sanam Peyvandi, Laura Ciarloni, Francesca Botta, Carole Bourquin, Curzio Rüegg
Tumor angiogenesis promotes tumor growth and metastasis. Anti-angiogenic therapy in combination with chemotherapy is used for the treatment of metastatic cancers, including breast cancer but therapeutic benefits are limited. Mobilization and accumulation of myeloid-derived suppressor cells (MDSC) during tumor progression and therapy have been implicated in metastasis formation and resistance to anti-angiogenic treatments. Here, we used the 4T1 orthotopic syngenic mouse model of mammary adenocarcinoma to investigate the effect of VEGF/VEGFR-2 axis inhibition on lung metastasis, MDSC and regulatory T cells (Tregs)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680746/novel-immune-checkpoint-blocker-to-treat-merkel-cell-carcinoma
#18
Lorenzo Galluzzi, Guido Kroemer
No abstract text is available yet for this article.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680745/vaccination-targeting-human-her3-alters-the-phenotype-of-infiltrating-t-cells-and-responses-to-immune-checkpoint-inhibition
#19
Takuya Osada, Michael A Morse, Amy Hobeika, Marcio A Diniz, William R Gwin, Zachary Hartman, Junping Wei, Hongtao Guo, Xiao-Yi Yang, Cong-Xiao Liu, Kensuke Kaneko, Gloria Broadwater, H Kim Lyerly
Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28680744/intratumoral-delivery-of-tumor-antigen-loaded-dc-and-tumor-primed-cd4-t-cells-combined-with-agonist-%C3%AE-gitr-mab-promotes-durable-cd8-t-cell-dependent-antitumor-immunity
#20
Zuqiang Liu, Xingxing Hao, Yi Zhang, Jiying Zhang, Cara D Carey, Louis D Falo, Walter J Storkus, Zhaoyang You
The progressive tumor microenvironment (TME) coordinately supports tumor cell expansion and metastasis, while it antagonizes the survival and (poly-)functionality of antitumor T effector cells. There remains a clear need to develop novel therapeutic strategies that can transform the TME into a pro-inflammatory niche that recruits and sustains protective immune cell populations. While intravenous treatment with tumor-primed CD4(+) T cells combined with intraperitoneal delivery of agonist anti-glucocorticoid-induced TNF receptor (α-GITR) mAb results in objective antitumor responses in murine early stage disease models, this approach is ineffective against more advanced tumors...
2017: Oncoimmunology
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