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https://www.readbyqxmd.com/read/29155997/immune-activation-and-benefit-from-avelumab-in-ebv-positive-gastric-cancer
#1
Anshuman Panda, Janice M Mehnert, Kim M Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Michael Kane, Levi Sokol, Mark N Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann W Silk, Joseph Aisner, Nancy Chan, Jyoti Malhotra, Melissa Frankel, Howard L Kaufman, Siraj Ali, Jeffrey S Ross, Eileen P White, Gyan Bhanot, Shridar Ganesan
Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS...
November 15, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29152083/programmed-cell-death-1-expression-is-associated-with-inferior-survival-in-patients-with-primary-central-nervous-system-lymphoma
#2
Hyunsoo Cho, Se Hoon Kim, Soo-Jeong Kim, Jong Hee Chang, Woo-Ick Yang, Chang-Ok Suh, Yu Ri Kim, Ji Eun Jang, June-Won Cheong, Yoo Hong Min, Jin Seok Kim
Programmed cell death 1 (PD-1) and its ligands PD-L1/PD-L2 have been shown to mediate immune evasion in various cancers, but their prognostic implications in patients with primary central nervous system lymphoma (PCNSL) are poorly understood. Therefore, we analyzed 76 PCNSL patients at initial diagnosis who were treated homogenously with high-dose methotrexate-based chemotherapy, and evaluated the prognostic roles of high immunohistochemical PD-1, PD-L1, and PD-L2 expression. The cut-off values for high PD-1 (≥ 70 cells/high power field [HPF]), PD-L1 (≥ 100 cells/HPF), and PD-L2 (≥ 100 cells/HPF) were determined by the area under the receiver operating characteristic curve...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29147618/programmed-cell-death-ligands-expression-in-phaeochromocytomas-and-paragangliomas-relationship-with-the-hypoxic-response-immune-evasion-and-malignant-behavior
#3
David J Pinato, James R Black, Sebastian Trousil, Roberto E Dina, Pritesh Trivedi, Francesco A Mauri, Rohini Sharma
The hypoxic response underlies the pathogenesis and malignant behavior of PCC/PGL. Regulation of PD-1 receptor-ligand signaling, a therapeutically actionable driver of the anti-tumor immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Tissue microarrays sections including consecutive cases diagnosed between 1983-2011 were stained for PD-L1 and 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29145737/pembrolizumab-as-first-line-therapy-for-metastatic-non-small-cell-lung-cancer
#4
Martin Reck
This review describes trials evaluating the monoclonal antibody pembrolizumab (an immunotherapy that blocks the interaction between programmed death-1 and programmed death-ligand 1 and 2 [PD-L1/PD-L2]) as first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the Phase III KEYNOTE-024 study, pembrolizumab monotherapy significantly improved progression-free survival (primary end point) and overall survival, and was associated with fewer adverse events compared with platinum-based chemotherapy in patients with NSCLC with PD-L1 expression on ≥50% of tumor cells...
November 17, 2017: Immunotherapy
https://www.readbyqxmd.com/read/29141050/differential-immunomodulation-in-human-monocytes-versus-macrophages-by-filarial-cystatin
#5
Gopinath Venugopal, Marion Mueller, Susanne Hartmann, Svenja Steinfelder
Parasitic nematodes have evolved powerful immunomodulatory molecules to enable their survival in immunocompetent hosts by subverting immune responses and minimizing pathological processes. One filarial molecule known to counteract host immune responses by inducing IL-10 and regulatory macrophages in mice is filarial cystatin. During a patent filarial infection monocytes encounter microfilariae in the blood, an event that occurs in asymptomatically infected filariasis patients that are immunologically hyporeactive...
2017: PloS One
https://www.readbyqxmd.com/read/29140105/durvalumab-in-non-small-cell-lung-cancer-patients-current-developments
#6
Laura Mezquita, David Planchard
Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy...
November 15, 2017: Future Oncology
https://www.readbyqxmd.com/read/29137331/hdac-inhibitors-enhance-the-immunotherapy-response-of-melanoma-cells
#7
Laurence Booth, Jane L Roberts, Andrew Poklepovic, John Kirkwood, Paul Dent
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29134128/a-preliminary-study-for-the-assessment-of-pd-l1-and-pd-l2-on-circulating-tumor-cells-by-microfluidic-based-chipcytometry
#8
Jinkai Teo, Anja Mirenska, Meihui Tan, Yifang Lee, Janice Oh, Lewis Z Hong, Richard Wnek, Yoon-Sim Yap, Shian-Jiun Shih, Ali Asgar S Bhagat, Chih-Liang Chin, David Ag Skibinski
Aim: Expression of PD-L1 in the tumor is associated with more favorable responses to anti-PD-1 therapy in multiple cancers. However, obtaining tumor biopsies for PD-L1 interrogation is an invasive procedure and challenging to assess repeatedly as the disease progresses. Materials & methods: Here we assess an alternative, minimally invasive approach to analyze blood samples for circulating tumor cells (CTCs) that have broken away from the tumor and entered the periphery...
November 2017: Future Science OA
https://www.readbyqxmd.com/read/29122656/programmed-death-1-ligands-pd-l1-and-pd-l2-show-distinctive-and-restricted-patterns-of-expression-in-lymphoma-subtypes
#9
Poonam K Panjwani, Vivek Charu, Monique DeLisser, Hernan Molina-Kirsch, Yasodha Natkunam, Shuchun Zhao
The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Since efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in over 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases respectively, and PD-L1 but not PD-L2 expression correlated with Epstein Barr Virus in tumor cells...
November 6, 2017: Human Pathology
https://www.readbyqxmd.com/read/29112015/pd-l1-and-pd-l2-are-differentially-expressed-by-macrophages-or-tumor-cells-in-primary-cutaneous-diffuse-large-b-cell-lymphoma-leg-type
#10
Sarah Menguy, Martina Prochazkova-Carlotti, Marie Beylot-Barry, Fréderic Saltel, Béatrice Vergier, Jean-Philippe Merlio, Anne Pham-Ledard
As checkpoint molecules' inhibition may represent a therapeutic option in relapsing cases, we assessed programmed death ligands' (PD-L1/PD-L2) expression in a series of 29 primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) cases. Double immunostaining for either PD-L1 or PD-L2 was associated either with PAX5 staining to evaluate tumor cells or with CD68 or CD163 staining for macrophages. The microenvironment of PCDLBCL-LT was characterized by immunostainings for CD3 (tumor-infiltrating lymphocytes), FOXP3 (regulatory T cells), programmed cell death-1, and CD33 (myeloid-derived suppressor cells)...
November 3, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29073638/intratumoural-pd-l1-expression-is-associated-with-worse-survival-of-patients-with-epstein-barr-virus-associated-gastric-cancer
#11
An Na Seo, Byung Woog Kang, Oh Kyoung Kwon, Ki Bum Park, Seung Soo Lee, Ho Young Chung, Wansik Yu, Han Ik Bae, Seong Woo Jeon, Hyojeung Kang, Jong Gwang Kim
BACKGROUND: This study investigated the clinical relevance and prognostic impact of the overall expression of programmed cell death protein ligand-1 (PD-L1) and programmed cell death protein ligand-2 (PD-L2), in patients with Epstein-Barr virus-associated gastric cancer (EBVaGC). METHODS: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, the expression status of PD-L1 and PD-L2 in 120 patients with EBVaGC identified by EBV-encoded RNA in situ hybridisation was retrospectively analysed using immunohistochemistry (IHC)...
October 26, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29069824/sensitive-detection-of-pd-l1-expression-on-circulating-epithelial-tumor-cells-cetcs-could-be-a-potential-biomarker-to-select-patients-for-treatment-with-pd-1-pd-l1-inhibitors-in-early-and-metastatic-solid-tumors
#12
Dorothea Sonja Schott, Monika Pizon, Ulrich Pachmann, Katharina Pachmann
BACKGROUND: The current cancer research strongly focuses on immune therapies, where the PD-1, with its ligands plays an important role. It is known that PD-L1 is frequently up-regulated in a number of different cancers and the relevance of this pathway has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed. We used a non-invasive, real-time biopsy for determining PD-L1 and PD-L2 expression in CETCs of solid cancer patients. METHODS: CETCs were determined from blood of 128 patients suffering from breast (72), prostate (27), colorectal (18) and lung (11) cancer...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29061851/hormonal-vitamin-d-upregulates-tissue-specific-pd-l1-and-pd-l2-surface-glycoprotein-expression-in-human-but-not-mouse
#13
Vassil Dimitrov, Manuella Bouttier, Giselle Boukhaled, Reyhaneh Salehi-Tabar, Radu Avramescu, Babak Memari, Benedeta Hasaj, Gergely L Lukacs, Connie Michele Krawczyk, John Howard White
PD-L1 (programmed death ligand 1) and PD-L2 are cell surface glycoproteins that interact with programmed death 1 (PD-1) on T cells to attenuate inflammation. PD-1 signaling has attracted intense interest for its role in a pathophysiological context: suppression of anti-tumor immunity. Similarly, vitamin D signaling has been increasingly investigated for its non-classical actions in stimulation of innate immunity and suppression of inflammatory responses. Here, we show that hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcriptional inducer of the human genes encoding PD-L1 and PD-L2 through the vitamin D receptor (VDR), a ligand-regulated transcription factor...
October 23, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29038297/tumor-pdcd1lg2-pd-l2-expression-and-the-lymphocytic-reaction-to-colorectal-cancer
#14
Yohei Masugi, Reiko Nishihara, Tsuyoshi Hamada, Mingyang Song, Annacarolina da Silva, Keisuke Kosumi, Mancang Gu, Yan Shi, Wanwan Li, Li Liu, Daniel Nevo, Kentaro Inamura, Yin Cao, Xiaoyun Liao, Katsuhiko Nosho, Andrew T Chan, Marios Giannakis, Adam J Bass, F Stephen Hodi, Gordon J Freeman, Scott J Rodig, Charles S Fuchs, Zhi Rong Qian, Jonathan A Nowak, Shuji Ogino
Expression of the immune checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell-mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by IHC in 823 colon and rectal carcinoma cases within two U...
November 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29038008/fibrinogen-cleavage-products-and-toll-like-receptor-4-promote-the-generation-of-programmed-cell-death-1-ligand-2-positive-dendritic-cells-in-allergic-asthma
#15
Minkyoung Cho, Jeong-Eun Lee, Hoyong Lim, Hyun-Woo Shin, Roza Khalmuratova, Garam Choi, Hyuk Soon Kim, Wahn Soo Choi, Young-Jun Park, Inbo Shim, Byung-Seok Kim, Chang-Yuil Kang, Jae-Ouk Kim, Shinya Tanaka, Masato Kubo, Yeonseok Chung
BACKGROUND: Inhaled protease allergens preferentially trigger TH2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of TH2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce TH2-favorable DCs in the airway remains unclear. OBJECTIVE: We sought to determine a subset of DCs responsible for TH2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway...
October 14, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28977839/genetic-defects-of-the-irf1-mediated-major-histocompatibility-complex-class-i-antigen-presentation-pathway-occur-prevalently-in-the-jak2-gene-in-non-small-cell-lung-cancer
#16
Tao Shen, Zhengming Chen, Zhizhuang Joe Zhao, Jie Wu
Recognition of major histocompatibility complex (MHC) class I antigens on tumor cells by cytotoxic T cells is involved in T cell-mediated tumor immune surveillance and immune checkpoint therapy. The interferon-γ (IFNγ)-IRF1 signaling pathway regulates MHC class I antigen presentation. To examine genetic defects of the IFNγ-IRF1 pathway in non-small cell lung cancer (NSCLC), we analyzed The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LuAd) and lung squamous cell carcinoma (LuSc) data. Loss-of-function (LOF) genetic alterations of the IFNγ-IRF1 pathway genes (IFNGR1, IFNGR2, JAK1, JAK2, STAT1, IRF1) were found in 64 (6...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28969052/pd-1-and-pd-l1-co-expression-predicts-favorable-prognosis-in-gastric-cancer
#17
Yanhua Wu, Donghui Cao, Limei Qu, Xueyuan Cao, Zhifang Jia, Tiancheng Zhao, Quan Wang, Jing Jiang
While the prognosis of gastric cancer (GC) remains poor, PD-1 and PD-L1/L2 are promising prognostic biomarkers. We evaluated PD-1 and PD-L1/L2 expression in tumor cells (TCs) and tumor-infiltrating immune cells (TIICs). We determined the Helicobacter pylori (Hp) and Epstein-Barr virus (EBV) infection status in a GC cohort (n=340), then analyzed the relationship between the expression of PD-1, PD-L1/L2 and GC prognosis. We found that PD-1, PD-L1, and PD-L2 mRNA levels were up-regulated in GC tissues, and were positively correlated with one another (P=0...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28963640/development-of-response-classifier-for-vascular-endothelial-growth-factor-receptor-vegfr-tyrosine-kinase-inhibitor-tki-in-metastatic-renal-cell-carcinoma
#18
Heounjeong Go, Mun Jung Kang, Pil-Jong Kim, Jae-Lyun Lee, Ji Y Park, Ja-Min Park, Jae Y Ro, Yong Mee Cho
Vascular endothelial growth factor receptor (VEGFR)-targeted therapy improved the outcome of metastatic renal cell carcinoma (mRCC) patients. However, a prediction of the response to VEGFR-tyrosine kinase inhibitor (TKI) remains to be elucidated. We aimed to develop a classifier for VEGFR-TKI responsiveness in mRCC patients. Among 101 mRCC patients, ones with complete response, partial response, or ≥24 weeks stable disease in response to VEGFR-TKI treatment were defined as clinical benefit group, whereas patients with <24 weeks stable disease or progressive disease were classified as clinical non-benefit group...
September 29, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28932634/pd1-positive-tumor-infiltrating-lymphocytes-are-associated-with-poor-clinical-outcome-after-pulmonary-metastasectomy-for-colorectal-cancer
#19
Dagmar Kollmann, Thomas Schweiger, Stefan Schwarz, Desislava Ignatova, Yun-Tsan Chang, Gerrit Lewik, Sebastian F Schoppmann, Wolfram Hoetzenecker, Walter Klepetko, Emmanuella Guenova, Konrad Hoetzenecker
Pulmonary metastasectomy (PM) is routinely performed in colorectal cancer (CRC) patients with oligometastatic spreading to the lungs. Patients with an aggressive tumor phenotype should be excluded from PM, since its benefit is outweighed by early tumor recurrence and impaired prognosis. Expression of PD-1 and its ligands are prognostic factors in a variety of primary tumors. However, their impact on patients' outcome in the setting of PM for CRC has not been evaluated before. 53 CRC patients with pulmonary metastases receiving PM with curative intent were included in this study...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28915646/interleukin-15-stimulates-natural-killer-cell-mediated-killing-of-both-human-pancreatic-cancer-and-stellate-cells
#20
Jonas R M Van Audenaerde, Jorrit De Waele, Elly Marcq, Jinthe Van Loenhout, Eva Lion, Johan M J Van den Bergh, Ralf Jesenofsky, Atsushi Masamune, Geert Roeyen, Patrick Pauwels, Filip Lardon, Marc Peeters, Evelien L J Smits
Pancreatic ductal adenocarcinoma (PDAC) is the 4(th) leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC)...
August 22, 2017: Oncotarget
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