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Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
October 21, 2016: Archives of Pharmacal Research
Liqing Wang, Suresh Kumar, Satinder Dahiya, Feng Wang, Jian Wu, Kheng Newick, Rongxiang Han, Arabinda Samanta, Ulf H Beier, Tatiana Akimova, Tricia R Bhatti, Benjamin Nicholson, Mathew P Kodrasov, Saket Agarwal, David E Sterner, Wei Gu, Joseph Weinstock, Tauseef R Butt, Steven M Albelda, Wayne W Hancock
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3...
October 15, 2016: EBioMedicine
C Franklin, E Livingstone, A Roesch, B Schilling, D Schadendorf
Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma...
September 2, 2016: European Journal of Surgical Oncology
Nitin Chakravarti, Doina Ivan, Van A Trinh, Isabella C Glitza, Jonathan L Curry, Carlos Torres-Cabala, Michael T Tetzlaff, Roland L Bassett, Victor G Prieto, Wen-Jen Hwu
Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival (OS) benefit. However, ipilimumab is associated with significant immune-related adverse events. We hypothesized that biomarker exploration of pretreatment tumor samples and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy...
October 20, 2016: Melanoma Research
Shouzheng Wang, Junling Li
In recent years, squamous non-small cell lung cancer (NSCLC) didn't progress much in chemotherapy or target therapy. However, immunotherapy has made breakthroughs in treating squamous NSCLC. Immunotherapy includes two main broad classes of immune checkpoint inhibitors and therapeutic vaccines. Immune checkpoint inhibitors, including anti cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and anti programmed death receptor 1 (PD-1) antibodies, have been tested in the phase II/III clinical trials and have demonstrated promising outcomes...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Xuhao Zhang, Shan Zhu, Tete Li, Yong-Jun Liu, Wei Chen, Jingtao Chen
Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the body's anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered "immune privileged" and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma...
October 16, 2016: Oncotarget
Patrizio Caturegli, Giulia Di Dalmazi, Martina Lombardi, Federica Grosso, H Benjamin Larman, Tatianna Larman, Giacomo Taverna, Mirco Cosottini, Isabella Lupi
Hypophysitis that develops in cancer patients treated with monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; an inhibitory molecule classically expressed on T cells) is now reported at an incidence of approximately 10%. Its pathogenesis is unknown, in part because no pathological examination of the pituitary gland has been reported to date. We analyzed at autopsy the pituitary glands of six cancer patients treated with CTLA-4 blockade, one with clinical and pathological evidence of hypophysitis, one with mild lymphocytic infiltration in the pituitary gland but no clinical signs of hypophysitis, and four with normal pituitary structure and function...
October 14, 2016: American Journal of Pathology
A K S Salama, S J Moschos
BACKGROUND: Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well characterized at preclinical and clinical levels...
October 13, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Hyeyoon Chang, Woon Yong Jung, Youngran Kang, Hyunjoo Lee, Aeree Kim, Han Kyeom Kim, Bong Kyung Shin, Baek-Hui Kim
Gastric adenocarcinoma is one of the most common causes of cancer-related death. In this study, we conducted immunohistochemical studies for PD-L1, PD-1, CTLA-4, and CD8 using tissue microarrays from 464 gastric cancer samples and evaluated the correlations between their expression, clinicopathologic factors, and five-year overall survival. PD-L1 and PD-1 expression was significantly correlated with several adverse prognostic pathologic factors, including higher T-stage, diffuse Lauren histologic type, and lymphatic invasion...
October 12, 2016: Oncotarget
Marco Donia, Magnus Pedersen, Inge Marie Svane
Patients with preexisting active autoimmune disorders were excluded from clinical trials of immune checkpoint inhibitors. However, patients with autoimmune disorders are diagnosed with cancer at least as frequently as the global population, and clinicians treating patients outside clinical trials have generally been reluctant to offer cancer immunotherapy to this patient group. In this brief article, we review the most recent literature on the efficacy and safety of CTLA-4- and PD-1-blocking antibodies in patients with preexisting autoimmune disorders...
October 11, 2016: Seminars in Immunopathology
Joana Felix, Bruno Cassinat, Raphael Porcher, Marie-Hélène Schlageter, Eve Maubec, Cécile Pages, Barouyr Baroudjian, Laurence Homyrda, Wahid Boukouaci, Ryad Tamouza, Martine Bagot, Anne Caignard, Antoine Toubert, Céleste Lebbé, Hélène Moins-Teisserenc
Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4 immunotherapy used in advanced melanoma, is an effective immunotherapy alone or combined with other agents but with few predictive biomarkers of response. Here, we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA antibodies and LDH as serum biomarkers of response and survival in a cohort of 77 advanced melanoma patients subjected to ipilimumab...
October 8, 2016: International Immunopharmacology
David Killock
No abstract text is available yet for this article.
November 2016: Nature Reviews. Clinical Oncology
Satoru Konnai, Shiro Murata, Kazuhiko Ohashi
Recently, dysfunction of antigen-specific T cells is well documented as T-cell exhaustion and has been defined by the loss of effector functions during chronic infections and cancer in human. The exhausted T cells are characterized phenotypically by the surface expression of immunoinhibitory receptors, such as programmed death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, there is still a fundamental lack of knowledge about the immunoinhibitory receptors in the fields of veterinary medicine...
October 8, 2016: Journal of Veterinary Medical Science
Sanjay B Rathod, Anuradha S Tripathy
BACKGROUND AND AIM: Literature on the role of Regulatory T cells (Tregs) in acute viral infections is limited. Having established that the Tregs in self-limiting hepatitis E infection are elevated and functional, this study has focused on characterizing the specificity, phenotypes and identifying the molecules or factors responsible for enhancement of Treg cells and abrogation of Treg-mediated suppression in hepatitis E. METHODS: HEV rORF2p specific (a) Treg frequency, subset analysis and expression of surface and intracellular markers on Tregs and CFSE based functional analysis by flow cytometry (b) key cytokines quantification by multiplex (c) suppressive functional assay in the presence of anti-TGF-β1 or anti-IL-10 or both antibodies or Transwell insert or in combination were performed on samples from 58 acute patients (AVH-E), 45 recovered individuals from hepatitis E and 55 controls...
October 6, 2016: Human Immunology
Markus V Heppt, Cecilia Dietrich, Saskia A Graf, Thomas Ruzicka, Julia K Tietze, Carola Berking
Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma...
2016: Oncology Research and Treatment
Hongxia Yan, Xianglian Hou, Tianhang Li, Li Zhao, Xiaozhou Yuan, Hongjun Fu, Ruijie Zhu
Metastatic melanoma is a rapidly progressing disease with high mortality rate and limited treatment options. Immunotherapy based on tumor-targeting cytotoxic T cell responses represents a promising strategy. To assist in its development, we examined the possibility and efficacy of using CD4(+) cytotoxic T cells. The regulatory mechanisms controlling CD4(+) T cell-mediated cytotoxicity were also investigated. We found that naturally occurring granzyme B and perforin-expressing CD4(+) cytotoxic T cells can be recovered from metastatic melanoma patients at significantly elevated frequencies compared to those from healthy controls...
October 5, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers...
September 30, 2016: Oncotarget
Melanie R Hassler, Walter Pulverer, Ranjani Lakshminarasimhan, Elisa Redl, Julia Hacker, Gavin D Garland, Olaf Merkel, Ana-Iris Schiefer, Ingrid Simonitsch-Klupp, Lukas Kenner, Daniel J Weisenberger, Andreas Weinhaeusel, Suzanne D Turner, Gerda Egger
Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK-) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK- ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters...
October 4, 2016: Cell Reports
Antonella Riccomi, Valentina Gesa, Alessandra Sacchi, Maria Teresa De Magistris, Silvia Vendetti
We have shown that cholera toxin (CT) and other cyclic AMP (cAMP)-elevating agents induce upregulation of the inhibitory molecule CTLA-4 in human resting CD4(+) T lymphocytes, which following the treatment acquired suppressive functions. In this study, we evaluated the effect of cAMP-elevating agents on human CD4(+)CD25(+) T cells, which include the T regulatory cells (Tregs) that play a pivotal role in the maintenance of immunological tolerance. We found that cAMP-elevating agents induce upregulation of CTLA-4 in CD4(+)CD25(-) and further enhance its expression in CD4(+)CD25(+) T cells...
2016: Frontiers in Immunology
Tristan Courau, Djamel Nehar-Belaid, Laura Florez, Béatrice Levacher, Thomas Vazquez, Faustine Brimaud, Bertrand Bellier, David Klatzmann
Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-β pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-β in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-β resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates...
June 16, 2016: JCI Insight
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