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Sophie Outh-Gauer, Marie Alt, Christophe Le Tourneau, Jérémy Augustin, Chloé Broudin, Cassandre Gasne, Thomas Denize, Haitham Mirghani, Elizabeth Fabre, Madeleine Ménard, Florian Scotte, Eric Tartour, Cécile Badoual
Cancer occurrence can be understood as the result of dysfunctions in immune tumoral microenvironment. Here we review the recent understandings of those microenvironment changes, regarding their causes and prognostic significance in head and neck (HN) carcinoma. We will focus on HN squamous cell cancer (SCC) and nasopharyngeal carcinomas (NPC). Their overall poor prognosis may be improved with immunotherapy in a subset of patients, as supported by current clinical trials. However, finding reliable markers of therapeutic response is crucial for patient selection, due to potential severe adverse reactions and high costs...
March 1, 2018: Cancer Treatment Reviews
Peter T Sage, Frank A Schildberg, Raymond A Sobel, Vijay K Kuchroo, Gordon J Freeman, Arlene H Sharpe
The programmed death (PD)-1 coinhibitory receptor regulates the balance between T cell activation and tolerance. Although the PD-1 ligands, PD-L1 and PD-L2, are expressed on a variety of cell types, the cell type-specific functions of PD-1 ligands in inducing signals through PD-1 are unknown. In this study, we use PD-L1 conditional knockout mice to investigate the cell type-specific functions of PD-L1. We demonstrate that PD-L1 expressed on dendritic cells (DCs), and to a lesser extent on B cells, attenuates the progression of experimental autoimmune encephalomyelitis and inhibits naive and effector T cells...
March 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Matthew A Lakins, Ehsan Ghorani, Hafsa Munir, Carla P Martins, Jacqueline D Shields
Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression...
March 5, 2018: Nature Communications
Andreas Seeber, Gerald Klinglmair, Josef Fritz, Fabian Steinkohl, Kai-Christian Zimmer, Friedrich Aigner, Wolfgang Horninger, Günther Gastl, Bettina Zelger, Andrea Brunner, Renate Pichler
Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 as predictive biomarker is still under critical evaluation. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy...
March 2, 2018: Cancer Science
Zuzana Saidak, Mony Chenda Morisse, Denis Chatelain, Chloé Sauzay, Aline Houessinon, Nelly Guilain, Marion Soyez, Bruno Chauffert, Stéphanie Dakpé, Antoine Galmiche
BACKGROUND/AIM: The squamous cell carcinoma antigen (SCCA), encoded by the genes SERPINB3/B4, is a tumour marker produced by head and neck squamous cell carcinoma (HNSCC). We aimed to examine SERPINB3/B4 mRNA levels and its clinical significance in the therapeutic context. MATERIALS AND METHODS: We retrieved mRNA expression levels, clinical, pathological and genomic data for 520 HNSCC from The Cancer Genome Atlas (TCGA). RESULTS: HNSCC tumours express high levels of SERPINB3/B4 mRNA...
March 2018: Anticancer Research
Yanxia Guo, Alice M Walsh, Mary Canavan, Mihir D Wechalekar, Suzanne Cole, Xuefeng Yin, Brittney Scott, Mathew Loza, Carl Orr, Trudy McGarry, Michele Bombardieri, Frances Humby, Susanna M Proudman, Costantino Pitzalis, Malcolm D Smith, Joshua R Friedman, Ian Anderson, Loui Madakamutil, Douglas J Veale, Ursula Fearon, Sunil Nagpal
Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development...
2018: PloS One
Dong Hoon Suh, Miseon Kim, Kyung Hun Lee, Keun Yong Eom, Maj Kamille Kjeldsen, Mansoor Raza Mirza, Jae Weon Kim
In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer...
March 2018: Journal of Gynecologic Oncology
Cesar E Ochoa, Richard W Joseph
Targeted agents form the backbone of most therapeutic strategies in advanced renal cell carcinoma (aRCC) but ultimately resistance develops and toxicity often leads to discontinuation of treatment, limiting the clinical benefits of these treatments. Nivolumab, a fully human IgG4 anti-PD-1 antibody, selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and provides a novel therapy option for patients with aRCC. In 2015, the pivotal phase III study CheckMate 025 led to the Food and Drug Administration approval of nivolumab in patients with aRCC who had received prior anti-angiogenic therapy, and in 2017, the phase III study CheckMate 214 showed that combined immunotherapy with nivolumab plus ipilimumab resulted in greater objective response rate and prolonged progression-free survival when compared with sunitinib in intermediate- and poor-risk patients with previously untreated aRCC...
2018: Journal of Kidney Cancer and VHL
Ana Costa, Yann Kieffer, Alix Scholer-Dahirel, Floriane Pelon, Brigitte Bourachot, Melissa Cardon, Philemon Sirven, Ilaria Magagna, Laetitia Fuhrmann, Charles Bernard, Claire Bonneau, Maria Kondratova, Inna Kuperstein, Andrei Zinovyev, Anne-Marie Givel, Maria-Carla Parrini, Vassili Soumelis, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4+ CD25+ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25High FOXP3High , through B7H3, CD73, and DPP4...
February 12, 2018: Cancer Cell
Frank Vari, David Arpon, Colm Keane, Mark S Hertzberg, Dipti Talaulikar, Sanjiv Jain, Qingyan Cui, Erica Han, Josh Tobin, Robert Bird, Donna Cross, Annette Hernandez, Clare Gould, Simone Birch, Maher K Gandhi
Much focus has been on the interaction of PD-L1 on malignant B-cells with PD-1 on effector T-cells in inhibiting anti-lymphoma immunity. We sought to establish the contribution of NK-cells and inhibitory CD163+ monocytes/macrophages in Hodgkin Lymphoma (cHL) and Diffuse Large B-cell Lymphoma (DLBCL). Levels of PD-1 on NK-cells were elevated in cHL relative to DLBCL. Notably, CD3- CD56hi CD16-ve NK-cells had substantially higher PD-1 expression relative to CD3- CD56dim CD16+ cells, and were expanded in blood and tissue, more marked in cHL than DLBCL patients...
February 15, 2018: Blood
Sara Mastaglio, Eric Wong, Travis Perera, Jane Ripley, Piers Blombery, Mark J Smyth, Rachel Koldej, David Ritchie
Natural killer (NKs) cells provide rapid responses to viral-infected and malignant cells, including acute myeloid leukemia (AML) blasts. The balance among inhibitory and activating signals, delivered by multiple interactions between ligands on target cells and NK receptors, determines the posture of the NK cell response to either one of target cell elimination or tolerance. The aim of this work was to study the influence of the differential expression of activating and inhibitory NK receptor ligands (NKRLs) by leukemic blasts on clinical outcome in newly diagnosed AML patients...
February 27, 2018: Blood Advances
Conor E Steuer, Christopher C Griffith, Sreenivas Nannapaneni, Mihir R Patel, Yuan Liu, Kelly R Magliocca, Mark W El-Deiry, Cynthia Cohen, Taofeek K Owonikoko, Dong M Shin, Zhuo Georgia Chen, Nabil F Saba
We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by immunohistochemistry on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0-4 within the tumor mass and peritumoral stroma...
February 13, 2018: Molecular Cancer Therapeutics
Alina Franzen, Timo J Vogt, Tim Müller, Jörn Dietrich, Andreas Schröck, Carsten Golletz, Peter Brossart, Friedrich Bootz, Jennifer Landsberg, Glen Kristiansen, Dimo Dietrich
Background: DNA methylation of the immune checkpoint gene PD-L1 has recently been shown to be associated with PD-L1 mRNA expression in various malignancies. This study aimed to investigate the association of PD-L1 and PD-L2 methylation with mRNA expression, immune cell infitration, protein expression and human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC) patients. Results: DNA methylation of PD-L1 and PD-L2 correlates inversely with mRNA expression ( PD-L1 : p ≤ 0...
January 2, 2018: Oncotarget
Bingxin Zheng, Tingting Ren, Yi Huang, Kunkun Sun, Shidong Wang, Xing Bao, Kuisheng Liu, Wei Guo
BACKGROUND: Immune checkpoint inhibitors have led to a breakthrough in solid tumor immunotherapy, but related studies on musculoskeletal tumors are few, especially for PD-L2. METHODS: We examined expression of three molecular effectors of the PD-1 axis in 234 patients with musculoskeletal tumors, including osteosarcoma, chondrosarcoma, synovial sarcoma, and giant cell tumor. Survival analyses and potential mechanisms were investigated in osteosarcoma per the Gene Expression Omnibus (GEO) and immunohistochemistry analyses...
February 6, 2018: Journal of Hematology & Oncology
Hyeyoon Chang, Jin Hwa Hong, Jae Kwan Lee, Hyun Woong Cho, Yung Taek Ouh, Kyung Jin Min, Kyeong A So
OBJECTIVE: Impaired local cellular immunity contributes to persistent human papillomavirus (HPV) infection and development of cervical intraepithelial neoplasia (CIN). Programmed death-1 (PD-1) and its ligands PD-ligand-1 (L1) and PD-L2 are negative regulators of T cell activity in various cancers, but few studies exist. The aim of this study was to determine the clinicopathologic and immunologic parameters (PD-1, PD-L1, and PD-L2) related to the persistence/recurrence of CIN after conization...
January 29, 2018: Journal of Gynecologic Oncology
Jorrit De Waele, Elly Marcq, Jonas Rm Van Audenaerde, Jinthe Van Loenhout, Christophe Deben, Karen Zwaenepoel, Erik Van de Kelft, David Van der Planken, Tomas Menovsky, Johan Mj Van den Bergh, Yannick Willemen, Patrick Pauwels, Zwi N Berneman, Filip Lardon, Marc Peeters, An Wouters, Evelien Lj Smits
Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade. In our experiments, poly(I:C) stimulated expression of both PD-L1 and PD-L2 on glioblastoma cells, and a pro-inflammatory secretome, including type I interferons (IFN) and chemokines CXCL9, CXCL10, CCL4 and CCL5...
2018: Oncoimmunology
Lea Kristin Röver, Heidrun Gevensleben, Jörn Dietrich, Friedrich Bootz, Jennifer Landsberg, Diane Goltz, Dimo Dietrich
Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas...
January 24, 2018: EBioMedicine
Margaretha G M Roemer, Robert A Redd, Fathima Zumla Cader, Christine J Pak, Sara Abdelrahman, Jing Ouyang, Stephanie Sasse, Anas Younes, Michelle Fanale, Armando Santoro, Pier Luigi Zinzani, John Timmerman, Graham P Collins, Radhakrishnan Ramchandren, Jonathon B Cohen, Jan Paul De Boer, John Kuruvilla, Kerry J Savage, Marek Trneny, Stephen Ansell, Kazunobu Kato, Benedetto Farsaci, Anne Sumbul, Philippe Armand, Donna S Neuberg, Geraldine S Pinkus, Azra H Ligon, Scott J Rodig, Margaret A Shipp
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial...
February 2, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Ellen W Hatch, Mary Beth Geeze, Cheyenne Martin, Mohamed E Salama, Karin Hartmann, Gregor Eisenwort, Katharina Blatt, Peter Valent, Jason Gotlib, Ji-Hyun Lee, Lu Chen, Heather H Ward, Diane S Lidke, Tracy I George
Mastocytosis is a rare disease with heterogeneous clinical manifestations and few effective therapies. Programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) protect tissues from immune-mediated damage and permit tumors to evade immune destruction. Therapeutic antibodies against PD-1 and PD-L1 are effective in the treatment of a variety of neoplasms. In the present study, we sought to systematically analyze expression of PD-1 and PD-L1 in a large number of patients with mastocytosis using immunohistochemistry and multiplex fluorescence staining...
February 13, 2018: Blood Advances
Yosuke Tanaka, Akiko Miyagi Maeshima, Junko Nomoto, Shinichi Makita, Suguru Fukuhara, Wataru Munakata, Dai Maruyama, Kensei Tobinai, Yukio Kobayashi
OBJECTIVES: We aimed at investigating the relationship between Classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBL), and gray zone lymphoma (GZL) with intermediate characteristics between cHL and PMBL, from the perspective of the aberration in programmed cell death 1 and the programmed death ligands (PDLs) network. METHODS: We explored the expression levels of PDLs and chromosomal anomalies in 67 cases: 34 cases with cHL, 20 with PMBL, and 13 with GZL, using immunohistochemical analyses and Fluorescence In Situ Hybridization (FISH)...
January 28, 2018: European Journal of Haematology
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