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https://www.readbyqxmd.com/read/28813417/cmtm6-maintains-the-expression-of-pd-l1-and-regulates-anti-tumour-immunity
#1
Marian L Burr, Christina E Sparbier, Yih-Chih Chan, James C Williamson, Katherine Woods, Paul A Beavis, Enid Y N Lam, Melissa A Henderson, Charles C Bell, Sabine Stolzenburg, Omer Gilan, Stuart Bloor, Tahereh Noori, David W Morgens, Michael C Bassik, Paul J Neeson, Andreas Behren, Phillip K Darcy, Sarah-Jane Dawson, Ilia Voskoboinik, Joseph A Trapani, Jonathan Cebon, Paul J Lehner, Mark A Dawson
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813410/identification-of-cmtm6-and-cmtm4-as-pd-l1-protein-regulators
#2
Riccardo Mezzadra, Chong Sun, Lucas T Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Meike E W Logtenberg, Maarten Slagter, Elisa A Rozeman, Ingrid Hofland, Annegien Broeks, Hugo M Horlings, Lodewyk F A Wessels, Christian U Blank, Yanling Xiao, Albert J R Heck, Jannie Borst, Thijn R Brummelkamp, Ton N M Schumacher
The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813164/pembrolizumab-in-patients-with-extensive-stage-small-cell-lung-cancer-results-from-the-phase-ib-keynote-028-study
#3
Patrick A Ott, Elena Elez, Sandrine Hiret, Dong-Wan Kim, Anne Morosky, Sanatan Saraf, Bilal Piperdi, Janice M Mehnert
Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry...
August 16, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28812434/-pemetrexed-sildenafil-via-autophagy-dependent-hdac-down-regulation-enhances-the-immunotherapy-response-of-nsclc-cells
#4
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of Class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment...
August 16, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28811971/preclinical-immunopet-ct-imaging-using-zr-89-labeled-anti-pd-l1-monoclonal-antibody-for-assessing-radiation-induced-pd-l1-upregulation-in-head-and-neck-cancer-and-melanoma
#5
Masahiro Kikuchi, David A Clump, Raghvendra M Srivastava, Lingyi Sun, Dexing Zeng, Julio A Diaz-Perez, Carolyn J Anderson, W Barry Edwards, Robert L Ferris
Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811967/il-18-receptor-marks-functional-cd8-t-cells-in-non-small-cell-lung-cancer
#6
Eleonora Timperi, Chiara Focaccetti, Daniela Gallerano, Mariangela Panetta, Sheila Spada, Enzo Gallo, Paolo Visca, Federico Venuta, Daniele Diso, Arsela Prelaj, Flavia Longo, Francesco Facciolo, Paola Nisticò, Vincenzo Barnaba
IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811961/pd-l1-immune-suppression-in-cancer-tumor-cells-or-host-cells
#7
Jan Willem Kleinovink, Thorbald van Hall, Ferry Ossendorp, Marieke F Fransen
Four recent publications reported the role of PD-L1 expression on host versus malignant cells within the tumor for PD-1/PD-L1 checkpoint blockade therapy. All four research groups harmoniously report: PD-L1 expressed by both host as well as tumor cells are capable of suppressing T cell functions. Thus, checkpoint therapy can be effective, if malignant cells do not express PD-L1.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811252/expression-of-alcam-cd166-and-pd-l1-cd274-independently-predicts-shorter-survival-in-malignant-pleural-mesothelioma
#8
Shingo Inaguma, Jerzy Lasota, Zengfeng Wang, Piotr Czapiewski, Renata Langfort, Janusz Rys, Joanna Szpor, Piotr Waloszczyk, Krzysztof Okoń, Wojciech Biernat, Hiroshi Ikeda, David S Schrump, Raffit Hassan, Markku Miettinen
Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4...
August 12, 2017: Human Pathology
https://www.readbyqxmd.com/read/28810147/macrophage-polarization-contributes-to-glioblastoma-eradication-by-combination-immunovirotherapy-and-immune-checkpoint-blockade
#9
Dipongkor Saha, Robert L Martuza, Samuel D Rabkin
Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Δ expressing murine IL-12 (G47Δ-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Δ-mIL12 cured most mice in two glioma models...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28810141/a-viro-immunotherapy-triple-play-for-the-treatment-of-glioblastoma
#10
John C Bell, Carolina S Ilkow
In this issue of Cancer Cell, Saha et al. systematically test and optimize combination therapy strategies in a challenging model of glioblastoma. Durable complete responses were seen only when an oncolytic virus expressing IL12 was coupled with anti-CTLA-4 and anti-PD-1 therapeutics.
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28808573/osimertinib-induced-interstitial-lung-disease-in-a-patient-with-non-small-cell-lung-cancer-pretreated-with-nivolumab-a-case-report
#11
Osamu Takakuwa, Tetsuya Oguri, Takehiro Uemura, Kazuki Sone, Satoshi Fukuda, Minami Okayama, Yoshihiro Kanemitsu, Hirotsugu Ohkubo, Masaya Takemura, Yutaka Ito, Ken Maeno, Akio Niimi
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene...
September 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28807336/programmed-death-1-pd-1-receptor-pd-1-ligand-pd-l1-expression-in-fumarate-hydratase-deficient-renal-cell-carcinoma
#12
Reza Alaghehbandan, Jan Stehlik, Kiril Trpkov, Cristina Magi-Galluzzi, Enric Condom Mundo, Maria Pane Foix, Daniel Berney, Mathilde Sibony, Saul Suster, Abbas Agaimy, Delia Perez Montiel, Kristyna Pivovarcikova, Kvetoslava Michalova, Ondrej Daum, Ondrej Ondic, Pavla Rotterova, Martin Dusek, Milan Hora, Michal Michal, Ondrej Hes
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR...
August 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28807048/response-to-single-agent-pd-1-inhibitor-after-progression-on-previous-pd-1-pd-l1-inhibitors-a-case-series
#13
Dylan J Martini, Aly-Khan A Lalani, Dominick Bossé, John A Steinharter, Lauren C Harshman, F Stephen Hodi, Patrick A Ott, Toni K Choueiri
BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28807004/predictive-role-of-pd-l1-expression-in-the-response-of-renal-medullary-carcinoma-to-pd-1-inhibition
#14
Quaovi Sodji, Kandy Klein, Kavuri Sravan, Jigarkumar Parikh
BACKGROUND: Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5 months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD-L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28806406/terminal-differentiation-of-t-cells-is-strongly-associated-with-cmv-infection-and-increased-in-hiv-positive-individuals-on-art-and-lifestyle-matched-controls
#15
Thijs Booiman, Ferdinand W Wit, Arginell F Girigorie, Irma Maurer, Davide De Francesco, Caroline A Sabin, Agnes M Harskamp, Maria Prins, Claudio Franceschi, Steven G Deeks, Alan Winston, Peter Reiss, Neeltje A Kootstra
HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank...
2017: PloS One
https://www.readbyqxmd.com/read/28806299/the-dynamic-and-transient-immune-microenvironment-in-locally-advanced-esophageal-adenocarcinoma-post-chemoradiation
#16
Ronan J Kelly, Ali H Zaidi, Matthew A Smith, Ashten N Omstead, Juliann E Kosovec, Daisuke Matsui, Samantha A Martin, Christina DiCarlo, E Day Werts, Jan F Silverman, David H Wang, Blair A Jobe
OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients...
August 10, 2017: Annals of Surgery
https://www.readbyqxmd.com/read/28803798/radiosynthesis-and-preclinical-pet-evaluation-of-89-zr-nivolumab-bms-936558-in-healthy-non-human-primates
#17
Erin L Cole, Joonyoung Kim, David J Donnelly, R Adam Smith, Daniel Cohen, Virginie Lafont, Paul E Morin, Richard Y-C Huang, Patrick L Chow, Wendy Hayes, Samuel Bonacorsi
Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types...
August 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28803728/distinct-cellular-mechanisms-underlie-anti-ctla-4-and-anti-pd-1-checkpoint-blockade
#18
Spencer C Wei, Jacob H Levine, Alexandria P Cogdill, Yang Zhao, Nana-Ama A S Anang, Miles C Andrews, Padmanee Sharma, Jing Wang, Jennifer A Wargo, Dana Pe'er, James P Allison
Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations...
August 9, 2017: Cell
https://www.readbyqxmd.com/read/28802922/biomarkers-of-nonmotor-symptoms-in-parkinson-s-disease
#19
Takuya Konno, Rana Hanna Al-Shaikh, Angela B Deutschländer, Ryan J Uitti
Biomarkers are helpful for early diagnosis, assessment of disorder severity, prognosis, and prediction of response to therapy. Given that early therapeutic intervention may be useful in forestalling or slowing neurodegenerative conditions, employing reliable biomarkers to identify asymptomatic individuals who are destined to develop clinical Parkinson's disease (PD) is critical. Two important observations have been repeatedly found in persons who eventually develop clinical PD: (1) significant neuronal loss occurs in the substantia nigra and (2) the presence of nonmotor symptoms (NMS)...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28802902/pseudomonas-aeruginosa-mannose-sensitive-hemagglutinin-injection-treated-cytokine-induced-killer-cells-combined-with-chemotherapy-in-the-treatment-of-malignancies
#20
Chaoqi Zhang, Zhen Zhang, Liping Wang, Jiaoling Han, Feng Li, Chunyi Shen, Hong Li, Lan Huang, Xuan Zhao, Dongli Yue, Jianmin Huang, Yan Yan, Yi Zhang
Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) injection serves as immunological adjuvant in clinical treatment of cancer patients. In present study, we investigated whether PA-MSHA injection enhanced the anti-tumor efficacy of CIK cells. Twenty patients with malignancies were enrolled in this retrospective clinical trial. They were divided into two groups: 10 patients received PA-MSHA treated CIK cells transfusion combined with chemotherapy, and other patients accepted CIK cells and chemotherapy...
August 10, 2017: International Immunopharmacology
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