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https://www.readbyqxmd.com/read/29467336/frameshift-events-predict-anti-pd-1-l1-response-in-head-and-neck-cancer
#1
Glenn J Hanna, Patrick Lizotte, Megan Cavanaugh, Frank C Kuo, Priyanka Shivdasani, Alexander Frieden, Nicole G Chau, Jonathan D Schoenfeld, Jochen H Lorch, Ravindra Uppaluri, Laura E MacConaill, Robert I Haddad
Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling...
February 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29464699/immune-checkpoint-blockade-combined-with-il-6-and-tgf-%C3%AE-inhibition-improves-the-therapeutic-outcome-of-mrna-based-immunotherapy
#2
Lukasz Bialkowski, Kevin Van der Jeught, Sanne Bevers, Patrick Tjok Joe, Dries Renmans, Carlo Heirman, Joeri L Aerts, Kris Thielemans
Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include, but are not limited to (1) adaptive expression of inhibitory checkpoint molecules in response to the pro-inflammatory environment and (2) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission...
February 21, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29463725/tim-3-co-stimulation-promotes-short-lived-effector-t-cells-restricts-memory-precursors-and-is-dispensable-for-t-cell-exhaustion
#3
Lyndsay Avery, Jessica Filderman, Andrea L Szymczak-Workman, Lawrence P Kane
Tim-3 is highly expressed on a subset of T cells during T cell exhaustion in settings of chronic viral infection and tumors. Using lymphocytic choriomeningitis virus (LCMV) Clone 13, a model for chronic infection, we found that Tim-3 was neither necessary nor sufficient for the development of T cell exhaustion. Nonetheless, expression of Tim-3 was sufficient to drive resistance to PD-L1 blockade therapy during chronic infection. Strikingly, expression of Tim-3 promoted the development of short-lived effector T cells, at the expense of memory precursor development, after acute LCMV infection...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29452091/expression-profiles-and-clinical-value-of-plasma-exosomal-tim-3-and-galectin-9-in-non-small-cell-lung-cancer
#4
Jianwei Gao, Xiangyu Qiu, Xinying Li, Hang Fan, Fang Zhang, Tangfeng Lv, Yong Song
Exosomes are membrane-bound, virus-size vesicles present in circulating blood. Tumor cells are avid producers of exosomes, which are thought to mimic molecular features of parent tumor cells. T-cell Immunoglobulin- and Mucin-domain-containing molecule 3 (Tim-3) is one of the next generation immune checkpoints and can be activated by its ligand Galectin-9, negatively regulating anti-tumor immune response. However, the characteristics of plasma exosomal Tim-3/Galectin-9 (Exo-T/G) in cancer remained unknown. Our study aimed to investigate the expression patterns and clinical value of plasma exosomal total protein (Exo-pro) and Exo-T/G in non-small cell lung caner (NSCLC)...
February 13, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29449693/tumor-cell-intrinsic-tim-3-promotes-liver-cancer-via-nf-%C3%AE%C2%BAb-il-6-stat3-axis
#5
Hualin Zhang, Yang Song, Huimin Yang, Zhiyan Liu, Lifen Gao, Xiaohong Liang, Chunhong Ma
T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), mediating immune exhaustion in tumor microenvironment, has become a promising target for tumor therapy. However, the exact mechanisms for tumor cell-intrinsic Tim-3 in tumor development and its potential contribution in Tim-3-targeted therapy strategy have not been elucidated yet. In this study, we showed that human liver cancer tissues contained high ratio of Tim-3-expressing hepatocytes, and cytokines rich in tumor microenvironment and HBV involved in Tim-3 upregulation in malignant hepatocytes...
February 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29444930/immunophenotyping-of-newly-diagnosed-and-recurrent-glioblastoma-defines-distinct-immune-exhaustion-profiles-in-peripheral-and-tumor-infiltrating-lymphocytes
#6
Malte Mohme, Simon Schliffke, Cecile L Maire, Alessandra Rünger, Laura Glau, Klaus C Mende, Jakob Matschke, Christina Gehbauer, Nuray Akyüz, Svenja Zapf, Mareike Holz, Miriam Schaper, Tobias Martens, Nils O Schmidt, Sven Peine, Manfred Westphal, Mascha Binder, Eva Tolosa, Katrin Lamszus
PURPOSE: Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T-cells (TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion. EXPERIMENTAL DESIGN: We used flow-cytometry and cytokine assays to profile TILs and blood lymphocytes (PBL) from GBM patients, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors...
February 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29440769/epithelial-mesenchymal-transition-emt-signature-is-inversely-associated-with-t-cell-infiltration-in-non-small-cell-lung-cancer-nsclc
#7
Young Kwang Chae, Sangmin Chang, Taeyeong Ko, Jonathan Anker, Sarita Agte, Wade Iams, Wooyoung M Choi, Kyoungmin Lee, Marcelo Cruz
Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores derived from a previously established 16 gene signature of canonical EMT markers...
February 13, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29434984/antitumor-effect-of-membrane-type-tim-3-on-hepatocellular-carcinoma-hepa1-6-cells-of-icr-mice
#8
Ju Liu, Haiying Sun, Dan Shen, Mingmin Wang, Zirong Wen
In the present study, the inhibitory effect of transmembrane Tim-3 on hepatocellular carcinoma Hepa1-6 cells and the potential application of Tim-3 on immune system of Institute of Cancer Research (ICR) mice loaded with Hepa1-6 hepatocellular carcinoma was investigated. The animal model was established via inoculation of Hepa1-6 hepatocarcinoma cells at the hind thigh of ICR mice. Recombinant vector plasmids were transfected at the same site for gene therapy by injection to observe the inhibitory effect of Tim-3 on tumor growth...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29433065/mir-330-5p-tim-3-axis-regulates-macrophage-m2-polarization-and-insulin-resistance-in-diabetes-mice
#9
Jiling Sun, Qiujing Huang, Shufa Li, Fanqing Meng, Xunhua Li, Xiaoyun Gong
Obesity is associated with a state of low-grade inflammatory response in adipose tissue, and contributes to the development of type 2 diabetes. Immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Therefore, adipose tissue promotes macrophage infiltration, resulting in local inflammation and insulin resistance. Tim-3 negatively regulates IFN-γ secretion and influences the ability to induce T cell tolerance in diabetes. MicroRNA contributes to the development of immunological tolerance and involves in macrophage polarization...
February 9, 2018: Molecular Immunology
https://www.readbyqxmd.com/read/29427415/ccr8-expression-defines-tissue-resident-memory-t-cells-in-human-skin
#10
Michelle L McCully, Kristin Ladell, Robert Andrews, Rhiannon E Jones, Kelly L Miners, Laureline Roger, Duncan M Baird, Mark J Cameron, Zita M Jessop, Iain S Whitaker, Eleri L Davies, David A Price, Bernhard Moser
Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is regulated by TCR engagement and the skin tissue microenvironment. To extend these observations, we examined the relationship between CCR8+ and CCR8- skin T cells in vivo. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue localization (CD103) and retention (CD69) markers, low levels of inhibitory receptors (programmed cell death protein 1, Tim-3, LAG-3), and a lack of senescence markers (CD57, killer cell lectin-like receptor subfamily G member 1)...
February 2, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29415983/14-3-3%C3%AE-delivered-by-hepatocellular-carcinoma-derived-exosomes-impaired-anti-tumor-function-of-tumor-infiltrating-t%C3%A2-lymphocytes
#11
Xiaochen Wang, Haiyuan Shen, Guangyan Zhangyuan, Ruyi Huang, Wenjie Zhang, Qifeng He, Kangpeng Jin, Han Zhuo, Zechuan Zhang, Jincheng Wang, Beicheng Sun, Xiaojie Lu
Increasing evidence shows that the anti-tumor functions of tumor-infiltrating T lymphocytes (TILs) were inhibited significantly, but the underlying mechanisms remain not fully understood. In this study, we found that 14-3-3ζ expression was up-regulated in hepatocellular carcinoma (HCC) cells and in TILs. TILs with 14-3-3ζ high-expression (14-3-3ζhigh) exhibited impaired activation (CD69), proliferation (Ki67) and anti-tumor functions compared to 14-3-3ζ low expression (14-3-3ζlow) TILs. Flow cytometry assay showed that compared with 14-3-3ζlow CD8+T cells, 14-3-3ζhigh ones exhibited higher frequency of exhausted phenotypes as measured by inhibitory receptors such as PD-1, TIM-3, LAG3, and CTLA-4...
February 7, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29399413/cellular-vaccination-of-mlh1-mice-an-immunotherapeutic-proof-of-concept-study
#12
Claudia Maletzki, Yvonne Saara Gladbach, Mohamed Hamed, Georg Fuellen, Marie-Luise Semmler, Jan Stenzel, Michael Linnebacher
Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1-/- knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29368793/different-aberrant-expression-pattern-of-immune-checkpoint-receptors-in-patients-with-ptcl-and-nk-t-cl
#13
Ziwei Liao, Xuewen Lv, Sichu Liu, Zifan He, Shaohua Chen, Liang Wang, Wenyu Li, Yangqiu Li
AIM: To better understand the T-cell immunodeficiency status in patients with peripheral T-cell lymphomas (PTCLs) and NK/T-cell lymphomas (NK/T-CLs), the T-cell inhibitory receptors expression pattern was investigated. METHODS: The expression levels of programmed death 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), B/T lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT) genes were detected in peripheral blood mononuclear cells (PBMCs) from patients and healthy volunteers by quantitative real-time-PCR, the correlation between different gene expression levels was analyzed...
January 25, 2018: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29359507/immune-checkpoint-inhibitors-in-cancer-therapy-a-focus-on-t-regulatory-cells
#14
REVIEW
Varun Sasidharan Nair, Eyad Elkord
Regulatory T cells (Tregs) play essential roles in immune homeostasis; however, their role in tumor microenvironment (TME) is not completely evident. Several studies reported that infiltration of Tregs into various tumor tissues promotes tumor progression by limiting antitumor immunity and supporting tumor immune evasion. Furthermore, in TME, Tregs include heterogeneous subsets of cells expressing different immunosuppressive molecules favoring tumor progression. For an effective cancer therapy, it is critical to understand the Treg heterogeneity and biology in the TME...
January 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29353075/btla-marks-a-less-cytotoxic-t-cell-subset-in-diffuse-large-b-cell-lymphoma-with-high-expression-of-checkpoints
#15
Lina Quan, Xiuwen Lan, Yuanyuan Meng, Xiuchen Guo, Yiwei Guo, Lina Zhao, Xue Chen, Aichun Liu
Immunotherapy has shown encouraging results in lymphoma. Pre-clinical and clinical trials have proven checkpoint blockade, such as PD-1 antibody, as an effective treatment for lymphoma, including diffuse large B-cell lymphoma (DLBCL). Combination of checkpoint blockades has emerged as a new way to treat lymphoma, however, the status of checkpoints expression and their function in DLBCL has not been fully elucidated yet. In this study, we examined the expression of BTLA, PD-1, TIM-3, LIGHT and LAG-3 in tumor micro-environmental T cells of DLBCL using flow cytometry, and compared the cytotoxicity and differentiation status of BTLA+ and BTLA- T-cells...
January 15, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29344269/early-and-partial-reduction-in-cd4-foxp3-regulatory-t-cells-during-colitis-associated-colon-cancer-induces-cd4-and-cd8-t-cell-activation-inhibiting-tumorigenesis
#16
Jonadab E Olguín, Itzel Medina-Andrade, Emmanuel Molina, Armando Vázquez, Thalia Pacheco-Fernández, Rafael Saavedra, Carlos Pérez-Plasencia, Yolanda I Chirino, Felipe Vaca-Paniagua, Luis E Arias-Romero, Emma B Gutierrez-Cirlos, Sonia A León-Cabrera, Miriam Rodriguez-Sosa, Luis I Terrazas
Colorectal cancer (CRC) is the second most commonly diagnosed cancer in women and the third in men in North America and Europe. CRC is associated with inflammatory responses in which intestinal pathology is caused by different cell populations including a T cell dysregulation that concludes in an imbalance between activated T (Tact) and regulatory T (Treg) cells. Treg cells are CD4+Foxp3+ cells that actively suppress pathological and physiological immune responses, contributing to the maintenance of immune homeostasis...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29344243/t-cell-immunoglobulin-and-mucin-domain-containing-protein-3-and-galectin-9-protein-expression-potential-prognostic-significance-in-esophageal-squamous-cell-carcinoma-for-chinese-patients
#17
Nan Hou, Jie Ma, Wei Li, Lingdi Zhao, Quanli Gao, Ling Mai
The aim of the present study was to investigate the expression levels of the T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) and galectin-9 proteins and their clinical value in esophageal squamous cell carcinoma (ESCC) in Chinese patients. The expression profiles of TIM-3 and galectin-9 in ESCC were determined by the immunohistochemical analysis of the postoperative pathological specimens of 45 patients with ESCC; a χ2 test was used to evaluate the association of TIM-3 and galectin-9 expression with clinicopathological parameters, in addition to univariate and multivariate Cox's proportional hazards model to analyze the prognostic value of the expression of TIM-3 and galectin-9 proteins...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29339375/tusc2-immunogene-synergizes-with-anti-pd1-through-enhanced-proliferation-and-infiltration-of-natural-killer-cells-in-syngeneic-kras-mutant-mouse-lung-cancer-models
#18
Ismail M Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veerabhadran Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji, Jack A Roth
Expression of the multikinase inhibitor encoded by tumor suppressor gene TUSC2 (also known as FUS1) is lost or decreased in non-small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti-PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti-PD-1...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29316433/tim-3-regulates-cd103-dendritic-cell-function-and-response-to-chemotherapy-in-breast-cancer
#19
Álvaro de Mingo Pulido, Alycia Gardner, Shandi Hiebler, Hatem Soliman, Hope S Rugo, Matthew F Krummel, Lisa M Coussens, Brian Ruffell
Intratumoral CD103+ dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103+ DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no evidence of toxicity. Combined efficacy was CD8+ T cell dependent and associated with increased granzyme B expression; however, TIM-3 expression was predominantly localized to myeloid cells in both human and murine tumors...
January 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29315553/acute-stimulation-generates-tim-3-expressing-th1-type-cd4-t-cells-that-persist-in-vivo-and-show-enhanced-effector-function
#20
Jacob V Gorman, John D Colgan
Tim-3 is a surface receptor expressed by Th1-type effector CD4 T cells, which are critical for defense against intracellular pathogens and have been implicated in autoimmune disease. Previous studies showed Tim-3 expression makes Th1 cells more susceptible to apoptosis and also marks functionally impaired T cells that arise due to chronic stimulation. However, other studies suggested Tim-3-expressing Th1 cells do not always have these properties. To further define the relationship between Tim-3 and Th1 cell function, we analyzed the characteristics of Th1 cells that expressed Tim-3 in response to brief stimulation in vitro or an acute viral infection in vivo...
January 9, 2018: Immunology
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