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https://www.readbyqxmd.com/read/28710313/ex-vivo-pd-l1-pd-1-pathway-blockade-reverses-dysfunction-of-circulating-cea-specific-t-cells-in-pancreatic-cancer-patients
#1
Yuan Chen, Shao-An Xue, Goran Hamid Mohammad, Stephen P Pereira, Emma Morris, Shahriar Behboudi
Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer (PC). In this study, we have characterised the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2 restricted peptide, pCEA691-699, isolated from the peripheral T cell repertoire of PC patients and sought to determine if ex vivo PD-L1 & TIM3 blockade could enhance CTL function. CD8(+) T cell lines were generated from peripheral blood mononuclear cells (PBMCs) of 18 HLA-A2(+) patients with PC and from 15 healthy controls...
July 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28686578/culling-of-apcs-by-inflammatory-cell-death-pathways-restricts-tim3-and-pd-1-expression-and-promotes-the-survival-of-primed-cd8-t-cells
#2
Rajen Patel, Kwangsin Kim, Bojan Shutinoski, Kristina Wachholz, Lakshmi Krishnan, Subash Sad
We evaluated the impact of premature cell death of antigen-presenting cells (APCs) by Caspase-1- and RipK3-signaling pathways on CD8(+) T-cell priming during infection of mice with Salmonella typhimurium (ST). Our results indicate that Caspase1 and RipK3 synergize to rapidly eliminate infected APCs, which does not influence the initial activation of CD8(+) T cells. However, the maintenance of primed CD8(+) T cells was greatly compromised when both these pathways were disabled. Caspase-1- and RipK3-signaling did not influence NF-κB signaling in APCs, but synergized to promote processing of IL-1 and IL-18...
July 7, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28648905/antibodies-against-immune-checkpoint-molecules-restore-functions-of-tumor-infiltrating-t-cells-in-hepatocellular-carcinomas
#3
Guoying Zhou, Dave Sprengers, Patrick P C Boor, Michail Doukas, Hannah Schutz, Shanta Mancham, Alexander Pedroza-Gonzalez, Wojciech G Polak, Jeroen de Jonge, Marcia Gaspersz, Haidong Dong, Kris Thielemans, Qiuwei Pan, Jan N M IJzermans, Marco J Bruno, Jaap Kwekkeboom
BACKGROUND & AIMS: Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), downregulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase anti-tumor immunity in patients with melanoma, non-small cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4(+) and CD8(+) T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised...
June 22, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28624961/phenotypic-and-functional-characterization-of-t-cells-in-white-matter-lesions-of-multiple-sclerosis-patients
#4
Gijsbert P van Nierop, Marvin M van Luijn, Samira S Michels, Marie-Jose Melief, Malou Janssen, Anton W Langerak, Werner J D Ouwendijk, Rogier Q Hintzen, Georges M G M Verjans
T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry...
June 17, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28615061/synergistic-effect-of-il-12-and-il-18-induces-tim3-regulation-of-%C3%AE-%C3%AE-t-cell-function-and-decreases-the-risk-of-clinical-malaria-in-children-living-in-papua-new-guinea
#5
Louis Schofield, Lisa J Ioannidis, Stephan Karl, Leanne J Robinson, Qiao Y Tan, Daniel P Poole, Inoni Betuela, Danika L Hill, Peter M Siba, Diana S Hansen, Ivo Mueller, Emily M Eriksson
BACKGROUND: γδ T cells are important for both protective immunity and immunopathogenesis during malaria infection. However, the immunological processes determining beneficial or detrimental effects on disease outcome remain elusive. The aim of this study was to examine expression and regulatory effect of the inhibitory receptor T-cell immunoglobulin domain and mucin domain 3 (TIM3) on γδ T cells. While TIM3 expression and function on conventional αβ T cells have been clearly defined, the equivalent characterization on γδ T cells and associations with disease outcomes is limited...
June 15, 2017: BMC Medicine
https://www.readbyqxmd.com/read/28600190/understanding-the-checkpoint-blockade-in-lung-cancer-immunotherapy
#6
REVIEW
Maria G Dal Bello, Angela Alama, Simona Coco, Irene Vanni, Francesco Grossi
Immunotherapies have changed the treatment strategy of some types of tumor including melanoma and, more recently, non-small-cell lung cancer (NSCLC). Immune checkpoints are crucial for the maintenance of self-tolerance and it is known that some tumors use checkpoint systems to evade antitumor immune response. The treatment of advanced NSCLC by immune-checkpoint blockade targeting the PD1/PDL1 and CTLA4 pathways has led to significant clinical benefit either as monotherapy or in combination therapy. Moreover, checkpoint receptors such as LAG3, TIM3 and KIRs are also being investigated as potential immunotherapeutic targets...
June 7, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28578092/construction-of-human-masp-2-ccp1-2sp-ccp2sp-sp-plasmid-dna-nanolipoplexes-and-the-effects-on-tuberculosis-in-bcg-infected-mice
#7
Qi Gao, Xinfang Dong, Yanping Luo, Guochao Zhang, Jinyu Shan, Qian Wang, Qi He, Lifeng Zhang, Jingqiu Wang, Bingdong Zhu, Xingming Ma
The lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. The serine protease of MASP-2 plays an essential role in complement activation of the lectin pathway. The C-terminal segment of MASP-2 is comprised of the CCP1-CCP2-SP domains, and is the crucial catalytic segment. However, what is the effect of CCP1-CCP2-SP domains in controlling chronic infection is unknown. In order to evaluate the potential impact of CCP1-CCP2-SP domains on tuberculosis, we constructed the human MASP-2 CCP1/2SP, CCP2SP and SP recombinant plasmids, and delivered these plasmids by DNA-DOTAP:cholesterol cationic nanolipoplexes to BCG-infected mice...
May 31, 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28515387/functional-polymorphisms-affecting-th1-differentiation-are-associated-with-the-severity-of-autoimmune-thyroid-diseases
#8
Naoya Inoue, Mikio Watanabe, Azusa Nakaguchi, Daishi Ueda, Hayaka Kawaguti, Yoh Hidaka, Yoshinori Iwatani
The prognosis for autoimmune thyroid diseases (AITDs), such as Hashimoto's disease (HD) and Graves' disease (GD), varies among patients. Interleukin (IL)-12 and IL-18 also induce Th1 differentiation, and SOCS1 (Suppressor of cytokine signaling 1) and TIM-3 (T cell immunoglobulin and mucin domain-3) are known to be negative regulators of Th1 cells. To clarify the association of functional polymorphisms in the IL12, IL12Rβ1, IL18, SOCS1 and TIM3 genes with the intractability and severity of autoimmune thyroid disease (AITD), we genotyped these polymorphisms in 151 GD patients, including 61 patients with intractable GD and 51 patients with GD in remission, in 140 HD patients, including 59 patients with severe HD and 55 patients with mild HD, and in 74 healthy controls...
May 16, 2017: Endocrine Journal
https://www.readbyqxmd.com/read/28447034/the-biomarkers-of-leukemia-stem-cells-in-acute-myeloid-leukemia
#9
REVIEW
Yahui Ding, Huier Gao, Quan Zhang
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by morphology and chromosome aberrations with high mortality. Leukemia stem cells (LSCs) in AML played important roles in leukemia initiation, progression, and were considered to be the root of chemotherapeutic drug resistance and disease relapse. The identification and targeting LSCs depended on membrane markers like CD34, CD38, CD123, TIM3, CD25, CD32 and CD96. In addition, the transcription factors were also therapeutic targets in eradicating LSCs, such as histone deacetylases (HDACs), NF-κB, HIF-1α and β-catenin...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28351582/defining-an-inflamed-tumor-immunophenotype-in-recurrent-metastatic-squamous-cell-carcinoma-of-the-head-and-neck
#10
Glenn J Hanna, Hongye Liu, Robert E Jones, Alyssa F Bacay, Patrick H Lizotte, Elena V Ivanova, Mark A Bittinger, Megan E Cavanaugh, Amanda J Rode, Jonathan D Schoenfeld, Nicole G Chau, Robert I Haddad, Jochen H Lorch, Kwok-Kin Wong, Ravindra Uppaluri, Peter S Hammerman
OBJECTIVES: Immune checkpoint inhibitors have demonstrated clinical benefit in recurrent, metastatic (R/M) squamous cell carcinoma of the head and neck (SSCHN), but lacking are biomarkers that predict response. We sought to define an inflamed tumor immunophenotype in this R/M SCCHN population and correlate immune metrics with clinical parameters and survival. METHODS: Tumor samples were prospectively acquired from 34 patients to perform multiparametric flow cytometry and multidimensional clustering analysis integrated with next-generation sequencing data, clinical parameters and outcomes...
April 2017: Oral Oncology
https://www.readbyqxmd.com/read/28323897/hcv-coinfection-contributes-to-hiv-pathogenesis-by-increasing-immune-exhaustion-in-cd8-t-cells
#11
Norma Rallón, Marcial García, Javier García-Samaniego, Noelia Rodríguez, Alfonso Cabello, Clara Restrepo, Beatriz Álvarez, Rosa García, Miguel Górgolas, José M Benito
BACKGROUND: There are several contributors to HIV-pathogenesis or insufficient control of the infection. However, whether HIV/HCV-coinfected population exhibits worst evolution of HIV-pathogenesis remains unclear. Recently, some markers of immune exhaustion have been proposed as preferentially upregulated on T-cells during HIV-infection. Herein, we have analyzed T-cell exhaustion together with several other contributors to HIV-pathogenesis that could be affected by HCV-coinfection. PATIENTS AND METHODS: Ninety-six patients with chronic HIV-infection (60 HIV-monoinfected and 36 HIV/HCV-coinfected), and 20 healthy controls were included in the study...
2017: PloS One
https://www.readbyqxmd.com/read/28267900/augmentation-of-hepatitis-c-virus-specific-immunity-and-sustained-virologic-response
#12
S Shrivastava, E Wilson, B Poonia, L Tang, A Osinusi, A Kohli, S Kottilil
Treatment for chronic hepatitis C virus (HCV) infection has rapidly evolved into interferon-free directly acting antiviral regimens (DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon-based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV-specific immunity in CHCV-GT-1-infected patients during treatment with sofosbuvir (SOF)+ribavirin (RBV)...
March 7, 2017: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/28257599/immunosuppressive-drugs-affect-interferon-ifn-%C3%AE-and-programmed-cell-death-1-pd-1-kinetics-in-patients-with-newly-diagnosed-autoimmune-hepatitis
#13
C R Grant, B S Holder, R Liberal, M A Heneghan, Y Ma, G Mieli-Vergani, D Vergani, M S Longhi
Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4(+) CD25(-) cells, isolated from the peripheral blood of treatment-naive patients with AIH...
July 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28236980/significance-of-immune-checkpoint-proteins-in-egfr-mutant-non-small-cell-lung-cancer
#14
Ross A Soo, Hye Ryun Kim, Bernadette Reyna Asuncion, Zul Fazreen, Mohamed Feroz Mohd Omar, Maria Cynthia Herrera, Joey Sze Yun Lim, Grace Sia, Richie Soong, Byoung-Chul Cho
OBJECTIVES: To characterize the expression of PD-L1, PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3) in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Samples from 90 patients with newly diagnosed advanced stage NSCLC harboring EGFR mutations and treated with first line EGFR tyrosine kinase inhibitors (TKI) within 3 months of diagnosis were stained for CTLA-4, PD-L1, PD-1, TIM-3 and CD3 expression by immunohistochemistry...
March 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28213366/tumor-infiltrating-and-peripheral-blood-t-cell-immunophenotypes-predict-early-relapse-in-localized-clear-cell-renal-cell-carcinoma
#15
Nicolas A Giraldo, Etienne Becht, Yann Vano, Florent Petitprez, Laetitia Lacroix, Pierre Validire, Rafael Sanchez-Salas, Alexandre Ingels, Stephane Marie Oudard, Audrey Moatti, Bénédicte Buttard, Sarah Bourras, Claire Germain, Xavier Cathelineau, Wolf-Herman Fridman, Catherine Sautes-Fridman
PURPOSE: The efficacy of PD-1 Checkpoint Blockade (ChB) as adjuvant therapy in localized clear cell Renal Cell Carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help to define which patients could benefit from ChB and to uncover new therapeutic targets. EXPERIMENTAL DESIGN: We performed multiparametric flow cytometry immunophenotypic analysis of T cells isolated from tumor tissue (TIL), adjacent non-malignant renal tissue (RIL) and peripheral blood (PBL), in a cohort of patients (n=40) with localized ccRCC...
February 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28186088/current-status-of-immunotherapy-for-gastrointestinal-stromal-tumor
#16
REVIEW
Y Tan, J C Trent, B A Wilky, D A Kerr, A E Rosenberg
Gastrointestinal stromal tumors (GIST) contain tumor-infiltrating immune cells and their presence provides an opportunity and rationale for developing effective forms of immunotherapy. The types of tumor-infiltrating inflammatory cells and relevant immune checkpoint inhibitors are the focus of active investigation. The most numerous tumor-infiltrating inflammatory cells are tumor-associated macrophages (TAMs) and CD3+ T cells. Studies have shown that patients with GISTs that harbor increased numbers of CD3+ T cells have better outcomes...
March 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28159737/stem-and-progenitor-cell-alterations-in-myelodysplastic-syndromes
#17
REVIEW
Aditi Shastri, Britta Will, Ulrich Steidl, Amit Verma
Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers are also seen in a stage-specific manner in human MDS samples as well as in murine models of the disease...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28158245/protein-kinase-c-theta-is-required-for-efficient-induction-of-il-10-secreting-t-cells
#18
Graham J Britton, Ruth E Mitchell, Bronwen R Burton, David C Wraith
Secretion of interleukin-10 (IL-10) by CD4+ T cells is an essential immunoregulatory mechanism. The work presented here assesses the role of the signaling molecule protein kinase C theta (PKCθ) in the induction of IL-10 expression in CD4+ T cells. Using wildtype and PKCθ-deficient Tg4 T cell receptor transgenic mice, we implemented a well-described protocol of repeated doses of myelin basic protein (MBP)Ac1-9[4Y] antigen to induce Tr1-like IL-10+ T cells. We find that PKCθ is required for the efficient induction of IL-10 following antigen administration...
2017: PloS One
https://www.readbyqxmd.com/read/28103502/tim3-gal9-interactions-between-t-cells-and-monocytes-result-in-an-immunosuppressive-feedback-loop-that-inhibits-th1-responses-in-osteosarcoma-patients
#19
Xiuzhong Li, Yanqing Chen, Xu Liu, Jin Zhang, Xu He, Guodong Teng, Dazhi Yu
The Tim3/Gal9 pathway is associated with immunosuppression and worse clinical outcome in multiple cancers. To illustrate the specific mechanism of Tim3/Gal9 interaction in osteosarcoma, we examined expression, function, and regulation of Tim3/Gal9 in various cells from osteosarcoma patients. Data showed that CD4(+) T cells, CD8(+) T cells, and monocytes from both peripheral blood and tumor of osteosarcoma patients contained high frequencies of Tim3(+) cells, while the Gal9 expression was primarily found in regulatory T cells (Tregs) from osteosarcoma patients and was elevated compared to that in non-cancer controls...
March 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28102051/t-cell-immunoglobulin-mucin-3-blockade-drives-an-antitumor-immune-response-in-head-and-neck-cancer
#20
Jian-Feng Liu, Si-Rui Ma, Liang Mao, Lin-Lin Bu, Guang-Tao Yu, Yi-Cun Li, Cong-Fa Huang, Wei-Wei Deng, Ashok B Kulkarni, Wen-Feng Zhang, Zhi-Jun Sun
T-cell immunoglobulin mucin 3 (TIM3) contributes to immune suppression during progression of many cancers, but the precise role of TIM3 in head and neck squamous cell carcinoma (HNSCC) is not clearly understood. In this study, we report that TIM3 expression was significantly up-regulated in patients with HNSCC and associated with lymph node metastasis. Additionally, TIM3 expression was increased in patients with recurrent HNSCC and patients with preradiotherapy or prechemotherapy. We also characterized CD8(+) T cells and CD11b(+) CD33(+) myeloid-derived suppressor cells (MDSCs) in human HNSCC, and found that their expression was positively correlated with TIM3 expression...
February 2017: Molecular Oncology
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