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https://www.readbyqxmd.com/read/28939757/pd-1-blockade-promotes-epitope-spreading-in-anticancer-cd8-t-cell-responses-by-preventing-fratricidal-death-of-subdominant-clones-to-relieve-immunodomination
#1
Arash Memarnejadian, Courtney E Meilleur, Christopher R Shaler, Khashayarsha Khazaie, Jack R Bennink, Todd D Schell, S M Mansour Haeryfar
The interactions between programmed death-1 (PD-1) and its ligands hamper tumor-specific CD8(+) T cell (TCD8) responses, and PD-1-based "checkpoint inhibitors" have shown promise in certain cancers, thus revitalizing interest in immunotherapy. PD-1-targeted therapies reverse TCD8 exhaustion/anergy. However, whether they alter the epitope breadth of TCD8 responses remains unclear. This is an important question because subdominant TCD8 are more likely than immunodominant clones to escape tolerance mechanisms and may contribute to protective anticancer immunity...
September 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28929191/overview-of-lag-3-expressing-il-10-producing-regulatory-t-cells
#2
Keishi Fujio, Kazuhiko Yamamoto, Tomohisa Okamura
Regulatory T cells (Treg cells) play crucial roles in the induction of peripheral tolerance to self- and foreign-antigens. IL-10-producing regulatory T cells (IL-10-producing Treg cells) constitute a Treg cell subset characterized by the production of high amounts of IL-10, cytokine-mediated immunosuppressive capabilities, and independence of Foxp3 expression for their suppressive activity. In the past decade, identifying naturally occurring IL-10-producing Treg cells was difficult due to the lack of suitable surface markers...
September 20, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28928158/characterization-of-the-immune-microenvironment-in-hepatocellular-carcinoma-hcc
#3
Mark Yarchoan, Dongmei Xing, Lan Luan, Haiying Xu, Rajni Sharma, Aleksandra Popovic, Timothy M Pawlik, Amy K Kim, Qingfeng Zhu, Elizabeth M Jaffee, Janis Taube, Robert A Anders
PURPOSE: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. EXPERIMENTAL DESIGN: To characterize the immune microenvironment in HCC, immunohistochemical (IHC) staining was performed for CD8 positive T lymphocytes, PD-1 positive and LAG-3 positive lymphocytes, CD163 positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. RESULTS: Expression of CD8 was reduced in tumor and expression of CD163 was reduced at the tumor interface...
September 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28912398/-therapeutic-cancer-vaccine-and-immune-checkpoint-inhibitor
#4
Kousaku Mimura, Koji Kono
Therapeutic cancer vaccine enhances a specific immune response against tumor cells in vivo, resulting in exertion of antitumor effects. On the other hand, immune checkpoint inhibitors promote the induction of tumor-specific T cells and also enhance the cytotoxic abilityof these T cells in tumor microenvironment. There is a possibilitythat immune checkpoint inhibitors enhance tumor immune responses induced bytherapeutic cancer vaccine, and it is expected that additive or synergistic effects will be obtained bythe combination of them...
September 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28904197/differential-inhibitory-receptor-expression-on-t-cells-delineates-functional-capacities-in-chronic-viral-infection
#5
Jeffrey E Teigler, Gennadiy Zelinskyy, Michael A Eller, Diane L Bolton, Mary Marovich, Alexander D Gordon, Aljawharah Alrubayyi, Galit Alter, Merlin L Robb, Jeffrey N Martin, Steven G Deeks, Nelson L Michael, Ulf Dittmer, Hendrik Streeck
Inhibitory receptors have been extensively described for their importance in regulating immune responses in chronic infections and cancers. Blocking the function of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 have shown promise for augmenting CD8 T cell activity and boosting pathogen-specific immunity. However, the prevalence of inhibitory receptors on CD4 T cells and their relative influence on CD4 T cell functionality in chronic HIV infection remains poorly described. We therefore determined and compared inhibitory receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on virus-specific CD4 and CD8 T cells in relation to their functional T cell profile...
September 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28901003/expression-of-tim-3-and-lag-3-in-extranodal-nk-t-cell-lymphoma-nasal-type
#6
Yuhua Feng, Meizuo Zhong, Yiping Liu, Leyuan Wang, Youhong Tang
OBJECTIVE: To investigate the expression of TIM-3 and LAG-3 in extranodal NK/T cell lymphoma, nasal type (ENKTL), and evaluate the clinical and prognostic significance of TIM-3 and LAG-3 in ENKTL. METHODS: A total of 61 human paraffin-embedded specimens including 41 ENKTL and 20 rhinitis were involved. We performed immunohistochemistry to detect the expression of TIM-3 and LAG-3. We analyzed correlation between expression of TIM-3 and LAG-3 and clinicopathological features of ENKTL...
September 13, 2017: Histology and Histopathology
https://www.readbyqxmd.com/read/28900677/tim-3-lag-3-and-tigit
#7
Nicole Joller, Vijay K Kuchroo
Co-inhibitory receptors play a key role in regulating T cell responses and maintaining immune homeostasis. Their inhibitory function prevents autoimmune responses but also restricts the ability of T cells to mount effective immune responses against tumors or persistent pathogens. T cells express a module of co-inhibitory receptors, which display great diversity in expression, structure, and function. Here, we focus on the co-inhibitory receptors Tim-3, Lag-3, and TIGIT and how they regulate T cell function, maintenance of self-tolerance, their role in regulating ongoing T cell responses at peripheral tissues, and their synergistic effects in regulating autoimmunity and antitumor responses...
September 13, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28899396/transcriptomic-meta-analysis-identifies-gene-expression-characteristics-in-various-samples-of-hiv-infected-patients-with-nonprogressive-disease
#8
Le-Le Zhang, Zi-Ning Zhang, Xian Wu, Yong-Jun Jiang, Ya-Jing Fu, Hong Shang
BACKGROUND: A small proportion of HIV-infected patients remain clinically and/or immunologically stable for years, including elite controllers (ECs) who have undetectable viremia (<50 copies/ml) and long-term nonprogressors (LTNPs) who maintain normal CD4(+) T cell counts for prolonged periods (>10 years). However, the mechanism of nonprogression needs to be further resolved. In this study, a transcriptome meta-analysis was performed on nonprogressor and progressor microarray data to identify differential transcriptome pathways and potential biomarkers...
September 12, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28886587/distinct-pattern-of-immune-tolerance-in-dendritic-cells-treated-with-lipopolysaccharide-or-lipoteichoic-acid
#9
Hyo Shin Yoon, Girak Kim, Young Jun Ju, In Su Cheon, Sun Woong Hong, Dong Wook Kim, Byung-Chul Park, Seung Hyun Han, Cheol-Heui Yun
Cytokine induction is often critical for the host defense during acute immune responses while, if not tightly regulated, it may cause an immunological pathology coincident with tissue damage. Despite the fact that gram-positive bacterial infection has become increasingly prevalent, immune modulation induced by lipoteichoic acid (LTA), the major cell wall component of gram-positive bacteria has not been studied thoroughly at the cellular level. In the current study, tolerance induction in mouse bone marrow-derived dendritic cells (BMDCs) treated with single or repeated stimulation of Staphylococcus aureus LTA was compared with those of Escherichia coli lipopolysaccharide (LPS)...
September 5, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28882621/antibodies-targeting-btla-or-tim-3-enhance-hiv-1-specific-t-cell-responses-in-combination-with-pd-1-blockade
#10
Katharina Grabmeier-Pfistershammer, Carmen Stecher, Markus Zettl, Sandra Rosskopf, Armin Rieger, Gerhard J Zlabinger, Peter Steinberger
Persistent stimulation with antigens derived from viruses that establish chronic infections or tumour antigens results in the exhaustion of T cells. Coinhibitory receptors like PD-1 and CTLA-4 function as immune checkpoints on exhausted T cells. Blocking these molecules with antibodies improve immunity to cancer cells. Immune checkpoint inhibitors targeting other coinhibitory receptors might have a similar role in improving T cell function and thus also utility in cancer therapy. Using HIV-specific T cells as a model for exhaustion we have evaluated the capacity of antibodies targeting TIM-3, BTLA, CD160, LAG-3 and CTLA-4 alone or in combination with a PD-1 antibody to enhance proliferation and cytokine production in response to Gag and Nef peptides...
September 4, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28880895/lag-3-potentiates-the-survival-of-mycobacterium-tuberculosis-in-host-phagocytes-by-modulating-mitochondrial-signaling-in-an-in-vitro-granuloma-model
#11
Bonnie L Phillips, Uma S Gautam, Allison N Bucsan, Taylor W Foreman, Nadia A Golden, Tianhua Niu, Deepak Kaushal, Smriti Mehra
CD4+ T-cell mediated Th1 immune responses are critical for immunity to TB. The immunomodulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4+ T-cells...
2017: PloS One
https://www.readbyqxmd.com/read/28869950/interleukin-10-gene-modified-dendritic-cell-induced-type-1-regulatory-t-cells-induce-transplant-tolerance-and-impede-graft-versus-host-disease-after-allogeneic-stem-cell-transplantation
#12
Jiangbo Wan, Fang Huang, Siguo Hao, Weiwei Hu, Chuanxu Liu, Wenhao Zhang, Xiaohui Deng, Linjun Chen, Liyuan Ma, Rong Tao
BACKGROUND/AIMS: Tr1 cells can induce peripheral tolerance to self- and foreign antigens, and have been developed as a therapeutic tool for the induction of tolerance to transplanted tissue. We explored the feasibility of generating Tr1 cells by using IL-10 gene-modified recipient DCs (DCLV-IL-10) to stimulate donor naive CD4+ T cells. We also investigated some biological properties of Tr1 cells. METHODS: DCLV-IL-10 were generated through DCs transduced with a lentivirus vector carrying the IL-10 gene, and Tr1 cells were produced by using DCLV-IL-10 to stimulate naive CD4+ T cells...
August 31, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28865357/check-point-inhibitors-as-therapies-for-infectious-diseases
#13
REVIEW
Maureen A Cox, Robert Nechanitzky, Tak W Mak
The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection...
August 30, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28800255/overexpression-of-lymphocyte-activation-gene-3-inhibits-regulatory-t-cell-responses-in-osteoarthritis
#14
Junjie Xia, Zhiming Ni, Jian Wang, Shu Zhu, Hong Ye
Lymphocyte activation gene-3 (LAG-3) is a CD4 homologue expressed on the surface of activated conventional T cells and regulatory T (Treg) cells. In conventional T cells, LAG-3 acts as an inhibitory receptor of T cell inflammation. However, the role of LAG-3 in Treg cells remains controversial. In this study, we investigated the effect of LAG-3 on Tregs in osteoarthritis (OA). We observed that the proportion of LAG-3-expressing cells in CD4(+)CD25(+/high) T cells and Foxp3(+)CD4(+)CD25(+/high) T cells were significantly upregulated in OA patients...
August 11, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/28765518/characterization-of-infiltrating-lymphocytes-in-human-benign-and-malignant-prostate-tissue
#15
Emelie Rådestad, Lars Egevad, Carl Jorns, Jonas Mattsson, Berit Sundberg, Silvia Nava, Bo-Göran Ericzon, Lars Henningsohn, Victor Levitsky, Michael Uhlin
Immune checkpoint blockade has shown promising results in numerous cancer types. However, in prostate cancer (PC), absent or limited responses have been reported. To investigate further, we compared the phenotype of infiltrating T-cells isolated from prostate tissue from patients with PC (n = 5), benign prostatic hyperplasia (BPH) (n = 27), BPH with concurrent PC (n = 4) and controls (n = 7). The majority of T-cells were CD8+ and had a CCR7-CD45RO+ effector memory phenotype. However, the yield of T-cells isolated from PC lesions was on average 20-fold higher than that obtained from control prostates...
July 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28761757/mechanisms-of-action-and-rationale-for-the-use-of-checkpoint-inhibitors-in-cancer
#16
REVIEW
Clemence Granier, Eleonore De Guillebon, Charlotte Blanc, Helene Roussel, Cecile Badoual, Elia Colin, Antonin Saldmann, Alain Gey, Stephane Oudard, Eric Tartour
The large family of costimulatory molecules plays a crucial role in regulation of the immune response. These molecules modulate TCR signalling via phosphorylation cascades. Some of the coinhibitory members of this family, such as PD-1 and CTLA-4, already constitute approved targets in cancer therapy and, since 2011, have opened a new area of antitumour immunotherapy. Many antibodies targeting other inhibitory receptors (Tim-3, VISTA, Lag-3 and so on) or activating costimulatory molecules (OX40, GITR and so on) are under evaluation...
2017: ESMO Open
https://www.readbyqxmd.com/read/28758198/mir-15a-16-deficiency-enhances-anti-tumor-immunity-of-glioma-infiltrating-cd8-t-cells-through-targeting-mtor
#17
Jiao Yang, Ronghua Liu, Yuting Deng, Jiawen Qian, Zhou Lu, Yuedi Wang, Dan Zhang, Feifei Luo, Yiwei Chu
MiR-15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor-infiltrating immune cells. In our study, using an orthotropic GL261 mouse glioma model, we found that miR-15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor-infiltrating CD8+ T cells. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells...
July 31, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28738020/resident-memory-t-cells-in-the-skin-mediate-durable-immunity-to-melanoma
#18
Brian T Malik, Katelyn T Byrne, Jennifer L Vella, Peisheng Zhang, Tamer B Shabaneh, Shannon M Steinberg, Aleksey K Molodtsov, Jacob S Bowers, Christina V Angeles, Chrystal M Paulos, Yina H Huang, Mary Jo Turk
Tissue-resident memory T (TRM) cells have been widely characterized in infectious disease settings; however, their role in mediating immunity to cancer remains unknown. We report that skin-resident memory T cell responses to melanoma are generated naturally as a result of autoimmune vitiligo. Melanoma antigen-specific TRM cells resided predominantly in melanocyte-depleted hair follicles and were maintained without recirculation or replenishment from the lymphoid compartment. These cells expressed CD103, CD69, and CLA (cutaneous lymphocyte antigen), but lacked PD-1 (programmed cell death protein-1) or LAG-3 (lymphocyte activation gene-3), and were capable of making IFN-γ (interferon-γ)...
April 14, 2017: Science Immunology
https://www.readbyqxmd.com/read/28679768/pd-1-%C3%A2-polyfunctional-t-cells-dominate-the-periphery-after-tumor-infiltrating-lymphocyte-therapy-for-cancer
#19
Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Barbara Szomolay, Sascha Ott, Garry Dolton, Rikke Lyngaa, Sine Reker Hadrup, Andrew K Sewell, Inge Marie Svane
Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TILs) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs one month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here we studied the dynamics of bulk tumor-reactive CD8(+) T cell populations in patients with metastatic melanoma following treatment with TILs. <p>Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8(+) T cells contained in serial blood samples of sixteen patients treated with TILs</p> <p>Results: Polyfunctional tumor-reactive CD8(+) T cells accumulated over time in the peripheral lymphocyte pool...
July 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28674001/delineation-of-an-immunosuppressive-gradient-in-hepatocellular-carcinoma-using-high-dimensional-proteomic-and-transcriptomic-analyses
#20
Valerie Chew, Liyun Lai, Lu Pan, Chun Jye Lim, Juntao Li, Raymond Ong, Camillus Chua, Jing Yao Leong, Kiat Hon Lim, Han Chong Toh, Ser Yee Lee, Chung Yip Chan, Brian K P Goh, Alexander Chung, Pierce K H Chow, Salvatore Albani
The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8(+) T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs)...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
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