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Margaretha G M Roemer, Ranjana H Advani, Robert A Redd, Geraldine S Pinkus, Yasodha Natkunam, Azra H Ligon, Courtney F Connelly, Christine J Pak, Christopher D Carey, Sarah E Daadi, Bjoern Chapuy, Daphne de Jong, Richard T Hoppe, Donna S Neuberg, Margaret A Shipp, Scott J Rodig
In classical Hodgkin Lymphoma (cHL), malignant Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple mechanisms, including perturbed antigen presentation and enhanced PD-1 signaling. HRS cell expression of the PD-1 ligands is attributable, in part, to copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) Amplification of PD-L1/PD-L2 is associated with advanced clinical stage and inferior progression-free survival (PFS) following frontline (induction) therapy. The relationships between altered expression of β2-microglobulin (β2M), MHC class I, and MHC class II by HRS cells, PD-L1/PD-L2 amplification, and clinical outcome in cHL are poorly defined...
October 13, 2016: Cancer Immunology Research
Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Rie Sakakibara, Hironori Ninomiya, Sophia Subat, Hiroko Nagano, Kimie Nomura, Sakae Okumura, Tomoko Shibutani, Yuichi Ishikawa
OBJECTIVES: Compared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients...
October 1, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Bianca Schuhmacher, Benjamin Rengstl, Claudia Döring, Julia Bein, Sebastian Newrzela, Uta Brunnberg, Hans Michael Kvasnicka, Martine Vornanen, Ralf Küppers, Martin-Leo Hansmann, Sylvia Hartmann
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior...
September 30, 2016: Oncotarget
Damian T Rieke, Sebastian Ochsenreither, Konrad Klinghammer, Tanguy Y Seiwert, Frederick Klauschen, Inge Tinhofer, Ulrich Keilholz
Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PD-L1) expression.A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma...
September 23, 2016: Oncotarget
Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R Rutkowski, Benjamin G Bitler, Michael J Allegrezza, Yuhki Yokoyama, Andrew V Kossenkov, James E Bradner, Jose R Conejo-Garcia, Rugang Zhang
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells...
September 13, 2016: Cell Reports
Julie George, Motonobu Saito, Koji Tsuta, Reika Iwakawa, Kouya Shiraishi, Andreas Scheel, Shinsuke Uchida, Shun-Ichi Watanabe, Ryo Nishikawa, Masayuki Noguchi, Martin Peifer, Iver Petersen, Se Jin Jang, Reinhard Buttners, Curtis C Harris, Jun Yokota, Roman K Thomas, Takashi Kohno
BACKGROUND: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined, whether CD274 is a target of recurrent genomic alterations. METHODS: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1), and SNP array analysis in 138 human SCLC cases (cohort 2)...
September 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Anna Buermann, Dorothee Römermann, Wiebke Baars, Joachim Hundrieser, Jürgen Klempnauer, Reinhard Schwinzer
BACKGROUND: The development of donor-reactive antibodies is regarded to be an important barrier limiting long-term outcome of allo- and xenografts. We asked whether enhanced signaling via the co-inhibitory receptor programmed cell death-1 (PD-1; CD279) can downregulate human B-cell activation. METHODS: Proliferation of human purified CD19(+) B cells was induced by in vitro stimulation with CpG oligodeoxynucleotides (CpG-B). To induce antibody production, peripheral blood mononuclear cells were co-cultured with the porcine B-cell line L23...
September 2016: Xenotransplantation
Agnieszka Ciomber, Iwona Mitrus, Wojciech Fidyk, Andrzej Smagur, Agata Chwieduk, Magdalena Glowala-Kosinska, Tomasz Czerw, Małgorzata Sobczyk-Kruszelnicka, Włodzimierz Mendrek, Maria Sadus-Wojciechowska, Jacek Najda, Jerzy Holowiecki, Sebastian Giebel
Regeneration of the bone marrow microenvironment after transplantation of allogeneic hematopoietic stem cells is poorly explored. The goal of our study was to investigate this process focusing on immunologic factors: concentrations of selected cytokines, expression of immunosuppressive proteins CD47 and CD274 on hematopoietic stem cells, and frequency of T regulatory lymphocytes (Tregs). Bone marrow samples were collected before transplantation, on the day of transplantation, and at the 1-year follow-up. As a control group, we used bone marrow from healthy donors...
August 12, 2016: Experimental Hematology
Emily T Camilleri, Michael P Gustafson, Amel Dudakovic, Scott M Riester, Catalina Galeano Garces, Christopher R Paradise, Hideki Takai, Marcel Karperien, Simon Cool, Hee-Jeong Im Sampen, A Noelle Larson, Wenchun Qu, Jay Smith, Allan B Dietz, Andre J van Wijnen
BACKGROUND: Clinical translation of mesenchymal stromal cells (MSCs) necessitates basic characterization of the cell product since variability in biological source and processing of MSCs may impact therapeutic outcomes. Although expression of classical cell surface markers (e.g., CD90, CD73, CD105, and CD44) is used to define MSCs, identification of functionally relevant cell surface markers would provide more robust release criteria and options for quality control. In addition, cell surface expression may distinguish between MSCs from different sources, including bone marrow-derived MSCs and clinical-grade adipose-derived MSCs (AMSCs) grown in human platelet lysate (hPL)...
2016: Stem Cell Research & Therapy
Anthony Markham
Atezolizumab (Tecentriq™)-a monoclonal antibody targeting programmed death ligand 1 (PD-L1 or CD274 antigen)-is being developed by Genentech as treatment for a variety of haematological malignancies and solid tumours. It been approved in the US as a second-line therapy for urothelial carcinoma and is awaiting approval as a second-line therapy for non-small cell lung cancer. This article summarizes the milestones in the development of atezolizumab leading to this first approval for urothelial carcinoma.
August 2016: Drugs
Lei Guo, Wenbin Li, Xinxin Zhu, Yun Ling, Tian Qiu, Lin Dong, Yi Fang, Hongying Yang, Jianming Ying
PURPOSE: To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression with a validated antibody and CD274 gene alternation in a large cohort of triple negative breast cancer (TNBC) and correlated with clinicopathological data and patients overall survival. METHODS: Immunohistochemistry and in situ mRNA hybridization was used to detect PD-L1 protein and mRNA expression in tumor tissues from 183 TNBC patients respectively...
2016: SpringerPlus
Yngvild Nuvin Blaker, Signe Spetalen, Marianne Brodtkorb, Ole Christian Lingjaerde, Klaus Beiske, Bjørn Østenstad, Birgitta Sander, Björn Engelbrekt Wahlin, Christopher Michael Melen, June Helen Myklebust, Harald Holte, Jan Delabie, Erlend Bremertun Smeland
The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time...
October 2016: British Journal of Haematology
Chengjun Sun, Haiyan Wei, Xiuli Chen, Zhuhui Zhao, Hongwei Du, Wenhui Song, Yu Yang, Miaoying Zhang, Wei Lu, Zhou Pei, Li Xi, Jian Yan, Dijing Zhi, Ruoqian Cheng, Feihong Luo
Type 1 diabetes (T1D) is an autoimmune disease that has strong contribution of genetic factors to its etiology. We aimed to assess the genetic association between non-HLA genes and T1D in a Chinese case-control cohort recruited from multiple centers consisting of 364 patients with T1D and 719 unrelated healthy children. We genotyped 55 single nucleotide polymorphisms (SNP) markers located in 16 non-HLA genes (VTCN1, PTPN22, CTLA4, SUMO4, CD274, IL2RA, INS, DHCR7, ERBB3, VDR, CYP27B1, CD69, CD276, PTPN2, UBASH3A, and IL2RB) using SNaPshot multiple single-base extension methods...
September 2016: Meta Gene
Marie-Paule Sablin, Coraline Dubot, Jerzy Klijanienko, Sophie Vacher, Lamia Ouafi, Walid Chemlali, Martial Caly, Xavier Sastre-Garau, Emmanuelle Lappartient, Odette Mariani, José Rodriguez, Thomas Jouffroy, Angélique Girod, Valentin Calugaru, Caroline Hoffmann, Rosette Lidereau, Frédérique Berger, Maud Kamal, Ivan Bieche, Christophe Le Tourneau
BACKGROUND: We aimed at identifying druggable molecular alterations at the RNA level from untreated HNSCC patients, and assessing their prognostic significance. METHODS: We retrieved 96 HNSCC patients who underwent primary surgery. Real-time quantitative RT-PCR was used to analyze a panel of 42 genes coding for major druggable proteins. Univariate and multivariate analyses were performed to assess the prognostic significance of overexpressed genes. RESULTS: Median age was 56 years [35-78]...
June 18, 2016: Oncotarget
Lai Fong Kok, Felix Marsh-Wakefield, Jacqueline E Marshall, Caitlin Gillis, Gary M Halliday, Scott N Byrne
The ultraviolet (UV) radiation contained in sunlight is a powerful immune suppressant. While exposure to UV is associated with protection from the development of autoimmune diseases, particularly multiple sclerosis, the precise mechanism by which UV achieves this protection is not currently well understood. Regulatory B cells play an important role in preventing autoimmunity and activation of B cells is a major way in which UV suppresses adaptive immune responses. Whether UV-protection from autoimmunity is mediated by the activation of regulatory B cells has never been considered before...
September 2016: Journal of Autoimmunity
Keisuke Kataoka, Yuichi Shiraishi, Yohei Takeda, Seiji Sakata, Misako Matsumoto, Seiji Nagano, Takuya Maeda, Yasunobu Nagata, Akira Kitanaka, Seiya Mizuno, Hiroko Tanaka, Kenichi Chiba, Satoshi Ito, Yosaku Watatani, Nobuyuki Kakiuchi, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Masashi Sanada, Hidehiro Itonaga, Yoshitaka Imaizumi, Yasushi Totoki, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Kyoko Masuda, Nagahiro Minato, Koichi Kashiwase, Koji Izutsu, Akifumi Takaori-Kondo, Yasushi Miyazaki, Satoru Takahashi, Tatsuhiro Shibata, Hiroshi Kawamoto, Yoshiki Akatsuka, Kazuya Shimoda, Kengo Takeuchi, Tsukasa Seya, Satoru Miyano, Seishi Ogawa
Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma...
June 16, 2016: Nature
Lauren C Chong, David D W Twa, Anja Mottok, Susana Ben-Neriah, Bruce W Woolcock, Yongjun Zhao, Kerry J Savage, Marco A Marra, David W Scott, Randy D Gascoyne, Ryan D Morin, Andrew J Mungall, Christian Steidl
Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24...
September 1, 2016: Blood
Chang Xian Li, Chang Chun Ling, Yan Shao, Aimin Xu, Xiang Cheng Li, Kevin Tak-Pan Ng, Xiao Bing Liu, Yuen Yuen Ma, Xiang Qi, Hui Liu, Jiang Liu, Oscar Wai Ho Yeung, Xin Xiang Yang, Qing Sheng Liu, Yin Fan Lam, Yuan Zhai, Chung Mau Lo, Kwan Man
BACKGROUND & AIMS: Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. METHODS: The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models...
May 28, 2016: Journal of Hepatology
Y Sunakawa, S Cao, N B Volz, M D Berger, D Yang, A Parekh, W Zhang, S Matsusaka, Y Ning, S Stremitzer, S Stintzing, A Sebio, S Okazaki, T Wakatsuki, M Azuma, M Watanabe, W Koizumi, A H Wu, H-J Lenz
Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set...
May 31, 2016: Pharmacogenomics Journal
Timothy M Shaver, Brian D Lehmann, J Scott Beeler, Chung-I Li, Zhu Li, Hailing Jin, Thomas P Stricker, Yu Shyr, Jennifer A Pietenpol
Triple-negative breast cancer (TNBC) and other molecularly heterogeneous malignancies present a significant clinical challenge due to a lack of high-frequency "driver" alterations amenable to therapeutic intervention. These cancers often exhibit genomic instability, resulting in chromosomal rearrangements that affect the structure and expression of protein-coding genes. However, identification of these rearrangements remains technically challenging. Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC...
August 15, 2016: Cancer Research
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