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https://www.readbyqxmd.com/read/29069302/mechanistic-overview-of-immune-checkpoints-to-support-the-rational-design-of-their-combinations-in-cancer-immunotherapy
#1
A Rotte, J Y Jin, V Lemaire
Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been immensely successful in the treatment of cancer. Among several checkpoint receptors of immune cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints for cancer immunotherapy...
October 24, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28987965/emerging-targets-in-cancer-immunotherapy
#2
REVIEW
Samantha Burugu, Amanda R Dancsok, Torsten O Nielsen
The first generation of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) targeted natural immune homeostasis pathways, co-opted by cancers, to drive anti-tumor immune responses. These agents led to unprecedented results in patients with previously incurable metastatic disease and may become first-line therapies for some advanced cancers. However, these agents are efficacious in only a minority of patients. Newer strategies are becoming available that target additional immunomodulatory mechanisms to activate patients' own anti-tumor immune responses...
October 5, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28923946/immunoreceptor-tyrosine-based-inhibitory-motif-dependent-functions-of-an-mhc-class-i-specific-nk-cell-receptor
#3
Michael D Bern, Diana L Beckman, Takashi Ebihara, Samantha M Taffner, Jennifer Poursine-Laurent, J Michael White, Wayne M Yokoyama
Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self-MHC-I. Self-MHC-I also "licenses" NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28754817/multifaceted-role-of-btla-in-the-control-of-cd8-t-cell-fate-after-antigen-encounter
#4
Krit Ritthipichai, Cara L Haymaker, Melisa Martinez, Andrew Aschenbrenner, Xiaohui Yi, Minying Zhang, Charuta Kale, Luis M Vence, Jason Roszik, Yared Hailemichael, Willem W Overwijk, Navin Varadarajan, Roza Nurieva, Laszlo G Radvanyi, Patrick Hwu, Chantale Bernatchez
Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8(+) TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8(+)BTLA(+)TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation...
October 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28734136/the-good-and-bad-of-targeting-cancer-associated-extracellular-matrix
#5
REVIEW
Sabina Sangaletti, Claudia Chiodoni, Claudio Tripodo, Mario P Colombo
The maintenance of tissue homeostasis requires extracellular matrix (ECM) remodeling. Immune cells actively participate in regenerating damaged tissues contributing to ECM deposition and shaping. Dysregulated ECM deposition characterizes fibrotic diseases and cancer stromatogenesis, where a chronic inflammatory state sustains the ECM increase. In cancer, the ECM fosters several steps of tumor progression, providing pro-survival and proliferative signals, promoting tumor cell dissemination via collagen fibers or acting as a barrier to impede drug diffusion...
July 19, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28675212/enzymatic-self-assembly-of-an-immunoreceptor-tyrosine-based-inhibitory-motif-itim
#6
Natsuko Yamagata, Xiaoyi Chen, Jie Zhou, Jie Li, Xuewen Du, Bing Xu
Here we show the first example of an immunoreceptor tyrosine-based inhibitory motif (ITIM), LYYYYL, as well as its enantiomeric or retro-inverso peptide, to self-assemble in water via enzyme-instructed self-assembly. Upon enzymatic dephosphorylation, the phosphohexapeptides become hexapeptides, which self-assemble in water to result in supramolecular hydrogels. This work illustrates a new approach to design bioinspired soft materials from a less explored, but important pool of immunomodulatory peptides.
July 21, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28638976/lilrb-receptor-mediated-regulation-of-myeloid-cell-maturation-and-function
#7
REVIEW
William van der Touw, Hui-Ming Chen, Ping-Ying Pan, Shu-Hsia Chen
The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited...
August 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28629373/blimp-1-impairs-t-cell-function-via-upregulation-of-tigit-and-pd-1-in-patients-with-acute-myeloid-leukemia
#8
Liuluan Zhu, Yaxian Kong, Jianhong Zhang, David F Claxton, W Christopher Ehmann, Witold B Rybka, Neil D Palmisiano, Ming Wang, Bei Jia, Michael Bayerl, Todd D Schell, Raymond J Hohl, Hui Zeng, Hong Zheng
BACKGROUND: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML...
June 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28515726/comparative-analysis-of-immune-checkpoint-molecules-and-their-potential-role-in-the-transmissible-tasmanian-devil-facial-tumor-disease
#9
Andrew S Flies, Nicholas B Blackburn, Alan Bruce Lyons, John D Hayball, Gregory M Woods
Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28515320/recognition-of-nectin-2-by-the-natural-killer-cell-receptor-t-cell-immunoglobulin-and-itim-domain-tigit
#10
Felix A Deuss, Benjamin S Gully, Jamie Rossjohn, Richard Berry
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on the surface of natural killer (NK) cells. TIGIT recognizes nectin and nectin-like adhesion molecules and thus plays a critical role in the innate immune response to malignant transformation. Although the TIGIT nectin-like protein-5 (necl-5) interaction is well understood, how TIGIT engages nectin-2, a receptor that is broadly over-expressed in breast and ovarian cancer, remains unknown. Here, we show that TIGIT bound to the immunoglobulin domain of nectin-2 that is most distal from the membrane with an affinity of 6 μm, which was moderately lower than the affinity observed for the TIGIT/necl-5 interaction (3...
July 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28511131/genetic-diversity-and-phylogenetic-analysis-of-the-orf5-gene-of-prrsv-from-central-china
#11
Liujun Zhang, Yan Feng, Darren P Martin, Jing Chen, Sixu Ma, Pingan Xia, Gaiping Zhang
To more fully understand the genetic diversity and molecular epidemiology of prevailing porcine reproductive and respiratory syndrome virus (PRRSV) in Henan province of China, 112 full-length ORF5 gene sequences, originating from Henan province between 2006 and 2015, were subjected to sequence variation and phylogenetic analysis. Phylogenetic analysis revealed that all Henan isolates belonged to the Type 2 genotype and could be further divided into three subgroups. Subgroup 1 and 2 viruses predominated in Henan and subgroup 2 overtook subgroup 1 as the most prevalent PRRSV between 2006 and 2015...
May 11, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28465343/itim-receptors-more-than-just-inhibitors-of-platelet-activation
#12
REVIEW
Carmen H Coxon, Mitchell J Geer, Yotis A Senis
Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoietic cells, including platelets. However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation...
June 29, 2017: Blood
https://www.readbyqxmd.com/read/28409541/a-dual-positive-and-negative-regulation-of-monocyte-activation-by-leukocyte-ig-like-receptor-b4-depends-on-the-position-of-the-tyrosine-residues-in-its-itims
#13
Mijeong Park, Robert W Liu, Hongyan An, Carolyn L Geczy, Paul S Thomas, Nicodemus Tedla
The leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory cell surface receptor, primarily expressed on mono-myeloid cells. It contains 2 C-type Ig-like extracellular domains and a long cytoplasmic domain that contains three intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Data suggest that LILRB4 suppresses Fc receptor-dependent monocyte functions via its ITIMs, but relative contributions of the three ITIMs are not characterised. To address this, tyrosine (Tyr) residues at positions 337, 389 and 419 were single, double or triple mutated to phenylalanine and stably transfected into a human monocytic cell line, THP-1...
May 2017: Innate Immunity
https://www.readbyqxmd.com/read/28374110/htlv-1-infection-and-neuropathogenesis-in-the-context-of-rag1-%C3%AE-c-rag1-hu-and-blt-mice
#14
Rashida Ginwala, Breanna Caruso, Zafar K Khan, Ajinkya Pattekar, Glen M Chew, Michael J Corley, Ronak Loonawat, Steven Jacobson, Sreesha Sreedhar, Lishomwa C Ndhlovu, Pooja Jain
To date, the lack of a suitable small animal model has hindered our understanding of Human T-cell lymphotropic virus (HTLV)-1 chronic infection and associated neuropathogenesis defined as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Balb/c-Rag1(-/-)γc(-/-) or Rag1 as well as Bone marrow-Liver-Thymic (BLT) mouse models for engraftment of human CD34(+) hematopoietic stem cells...
September 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28332308/ceacam1-long-isoform-has-opposite-effects-on-the-growth-of-human-mastocytosis-and-medullary-thyroid-carcinoma-cells
#15
Chiyuki Ueshima, Tatsuki R Kataoka, Yusuke Takei, Masahiro Hirata, Akihiko Sugimoto, Mitsuyoshi Hirokawa, Yoshimichi Okayama, Richard S Blumberg, Hironori Haga
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed in a number of tumor cell types. The immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing isoforms of this molecule which possess a long cytoplasmic tail (CEACAM1-L) generally play inhibitory roles in cell function by interacting with Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and/or SHP-2. Src family kinases (SFKs) are also known to bind to and phosphorylate CEACAM1-L isoforms. Here, we report that CEACAM1 was uniquely expressed at high levels in both human neoplastic mast cells (mastocytosis) and medullary thyroid carcinoma cell (MTC) lines, when compared with their expression in nonneoplastic mast cells or nonneoplastic C cells...
April 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28127756/absence-of-dcir1-reduces-the-mortality-rate-of-endotoxemic-hepatitis-in-mice
#16
Toshifumi Ishiguro, Tetsuya Fukawa, Kotaro Akaki, Koji Nagaoka, Tatsuki Takeda, Yoichiro Iwakura, Kayo Inaba, Kazuhiko Takahara
Dendritic cell immunoreceptor (DCIR) is a C-type lectin with an immunoreceptor tyrosine-based inhibitory motif (ITIM). Mice lacking DCIR1 (Dcir1(-/-) mice) show higher susceptibility to chronic arthritis with increasing age, suggesting that DCIR1 is involved in immune modulation via its ITIM. However, the role of DCIR1 in acute immune responses is not clear. In this study, we explored its role in acute experimental hepatitis. Upon injection of d-galactosamine and lipopolysaccharide, Dcir1(-/-) mice showed decreased mortality rates and serum levels of alanine aminotransferase...
April 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28108989/tigit-signalling-pathway-negatively-regulates-cd4-t-cell-responses-in-systemic-lupus-erythematosus
#17
Lie Mao, Hongyan Hou, Shiji Wu, Yu Zhou, Juan Wang, Jing Yu, Xiaohui Wu, Yanfang Lu, Liyan Mao, Munyemana Jean Bosco, Feng Wang, Ziyong Sun
B-lymphocyte hyperactivity in systemic lupus erythematosus (SLE) is T-cell-dependent, and CD4(+) T-cell activation is essential to SLE pathogenesis. However, the mechanism of the deregulation of CD4(+) T cells in SLE is largely unknown. T-cell immunoglobulin and ITIM domain (TIGIT) is a new inhibitory receptor preferentially expressed on activated CD4(+) T cells. Here, we address the role of TIGIT in the pathogenesis of SLE. Our results showed that TIGIT expression on CD4(+) T cells was significantly elevated in patients with SLE and highly correlated with the activity of the disease...
July 2017: Immunology
https://www.readbyqxmd.com/read/28089363/pertussis-toxin-targets-the-innate-immunity-through-dap12-fcr%C3%AE-and-myd88-adaptor-proteins
#18
Vongsavanh Phongsisay, Ei'ichi Iizasa, Hiromitsu Hara, Hiroki Yoshida
Activation of the innate immunity by adjuvants, such as pertussis toxin (PTX), in the presence of autoreactive lymphocytes and antigen mimicry is sufficient to trigger autoimmunity. Toll-like, C-type lectin, and immunglobulin-like receptors play an important role in the innate immunity by sensing a variety of microbial products through several adaptor proteins, including MyD88, DAP12, and FcRγ. This study investigated the interaction between PTX and innate immune components. The direct interactions between coated PTX and receptor-fusion proteins were examined using ELISA-based binding assays...
December 30, 2016: Immunobiology
https://www.readbyqxmd.com/read/28046066/htlv-1-bzip-factor-enhances-t-cell-proliferation-by-impeding-the-suppressive-signaling-of-co-inhibitory-receptors
#19
Haruka Kinosada, Jun-Ichirou Yasunaga, Kazuya Shimura, Paola Miyazato, Chiho Onishi, Tomonori Iyoda, Kayo Inaba, Masao Matsuoka
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28030587/cd5-ck2-signaling-modulates-erk-activation-and-thymocyte-survival
#20
Carlos A Mier-Aguilar, Kevin S Cashman, Chander Raman, Gloria Soldevila
CD5 is well recognized for its importance in thymic selection. Although this property of CD5 has been attributed to its ITIM-domain dependent regulation of TCR-signal strength, the mechanism has not been established. A second major signaling domain within the cytoplasmic tail of CD5 is a CK2 binding/activation domain (CD5-CK2BD). Using a gene-targeted mouse in which the CD5-CK2BD is selectively ablated (CD5-ΔCK2BD), we determined that loss of function of CD5-CK2 signaling in a MHC-II selecting TCR transgenic (OT-II) mouse resulted in decrease in double positive (DP) thymocytes, which correlated with enhanced apoptosis...
2016: PloS One
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