المؤلفون: Wescott, Elizabeth, Sun, Xiaopeng, Gonzalez-Ericsson, Paula, Hanna, Ann, Taylor, Brandie, Sanchez, Violeta, Bronzini, Juliana, Opalenik, Susan, Sanders, Melinda, Wulfkuhle, Julia, Gallagher, Rosa, Gomez, Henry, Isaacs, Claudine, Bharti, Vijaya, Wilson, John, Ballinger, Tarah, Santa-Maria, Cesar, Shah, Payal, Dees, Elizabeth, Lehmann, Brian, Abramson, Vandana, Brown Swigart, Lamorna, van ˈt Veer, Laura, Petricoin, Emanuel, Pietenpol, Jennifer, Balko, Justin, Esserman, Laura, Hirst, Gillian

المصدر: Cancer Research Communications. 4(4)

مصطلحات موضوعية: V-Set Domain-Containing T-Cell Activation Inhibitor 1, Animals, Humans, Mice, Female, Cell Line, Tumor, Immunotherapy, Triple Negative Breast Neoplasms, Immune Checkpoint Inhibitors, Breast Neoplasms, B7-H1 Antigen, Epithelial Cells, Gene Expression Regulation, Neoplastic

الوصف: UNLABELLED: Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1kn0s65rTest
https://escholarship.org/content/qt1kn0s65r/qt1kn0s65r.pdfTest

المؤلفون: Saha, Asim, Taylor, Patricia A, Lees, Christopher J, Panoskaltsis-Mortari, Angela, Osborn, Mark J, Feser, Colby J, Thangavelu, Govindarajan, Melchinger, Wolfgang, Refaeli, Yosef, Hill, Geoffrey R, Munn, David H, Murphy, William J, Serody, Jonathan S, Maillard, Ivan, Kreymborg, Katharina, van den Brink, Marcel, Dong, Chen, Huang, Shuyu, Zang, Xingxing, Allison, James P, Zeiser, Robert, Blazar, Bruce R

المصدر: JCI Insight. 4(19)

مصطلحات موضوعية: Transplantation, Stem Cell Research, Rare Diseases, Hematology, Animals, Bone Marrow Transplantation, Cell Line, Tumor, Cell Proliferation, Cytokines, Disease Models, Animal, Female, Gastrointestinal Tract, Graft vs Host Disease, Lung, Lymphoma, Metabolic Networks and Pathways, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Oxygen Consumption, T-Lymphocytes, Tissue Donors, Transcriptome, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Bone marrow transplantation, Immunology, T cells

الوصف: B7-H4 is a negative regulatory B7 family member. We investigated the role of host and donor B7-H4 in regulating acute graft-versus-host disease (GVHD). Allogeneic donor T cells infused into B7-H4-/- versus WT recipients markedly accelerated GVHD-induced lethality. Chimera studies pointed toward B7-H4 expression on host hematopoietic cells as more critical than parenchymal cells in controlling GVHD. Rapid mortality in B7-H4-/- recipients was associated with increased donor T cell expansion, gut T cell homing and loss of intestinal epithelial integrity, increased T effector function (proliferation, proinflammatory cytokines, cytolytic molecules), and reduced apoptosis. Higher metabolic demands of rapidly proliferating donor T cells in B7-H4-/- versus WT recipients required multiple metabolic pathways, increased extracellular acidification rates (ECARs) and oxygen consumption rates (OCRs), and increased expression of fuel substrate transporters. During GVHD, B7-H4 expression was upregulated on allogeneic WT donor T cells. B7-H4-/- donor T cells given to WT recipients increased GVHD mortality and had function and biological properties similar to WT T cells from allogeneic B7-H4-/- recipients. Graft-versus-leukemia responses were intact regardless as to whether B7-H4-/- mice were used as hosts or donors. Taken together, these data provide new insights into the negative regulatory processes that control GVHD and provide support for developing therapeutic strategies directed toward the B7-H4 pathway.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/93d3n7ctTest

المؤلفون: Zhu, Dihan, Pan, Chaoyun, Sheng, Jingxue, Liang, Hongwei, Bian, Zhen, Liu, Yuan, Trang, Phong, Wu, Jianguo, Liu, Fenyong, Zhang, Chen-Yu, Zen, Ke

المصدر: Nature Microbiology. 3(4)

مصطلحات موضوعية: Microbiology, Biological Sciences, Infectious Diseases, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Genetics, Aetiology, 2.2 Factors relating to the physical environment, Infection, Cell Differentiation, Cellular Reprogramming, Cytomegalovirus, Hematopoietic Stem Cells, Host-Pathogen Interactions, Humans, Immune Tolerance, Interleukin-10, Monocytes, Nitric Oxide, Nitric Oxide Synthase Type II, STAT3 Transcription Factor, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Virus Latency, Medical Microbiology

الوصف: The precise cell type hosting latent human cytomegalovirus (HCMV) remains elusive. Here, we report that HCMV reprogrammes human haematopoietic progenitor cells (HPCs) into a unique monocyte subset to achieve latency. Unlike conventional monocytes, this monocyte subset possesses higher levels of B7-H4, IL-10 and inducible nitric oxide synthase (iNOS), a longer lifespan and strong immunosuppressive capacity. Cell sorting of peripheral blood from latently infected human donors confirms that only this monocyte subset, representing less than 0.1% of peripheral mononuclear cells, is HCMV genome-positive but immediate-early-negative. Mechanistic studies demonstrate that HCMV promotes the differentiation of HPCs into this monocyte subset by activating cellular signal transducer and activator of transcription 3 (STAT3). In turn, this monocyte subset generates a high level of nitric oxide (NO) to silence HCMV immediate-early transcription and promote viral latency. By contrast, the US28-knockout HCMV mutant, which is incapable of activating STAT3, fails to reprogramme the HPCs and achieve latency. Our findings reveal that via activating the STAT3-iNOS-NO axis, HCMV differentiates human HPCs into a longevous, immunosuppressive monocyte subset for viral latency.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/23t5h6fbTest

المؤلفون: Kyoko Yoshida, Naoya Yamashita, Noriko Sanada, Ryoichi Kizu, Yuichiro Kanno

المصدر: Biological and Pharmaceutical Bulletin. 2022, 45(6):793

المؤلفون: Zhaopei Liu, Kaifeng Jin, Han Zeng, Fei Shao, Yuan Chang, Yiwei Wang, Le Xu, Zewei Wang, Xingang Cui, Yu Zhu, Jiejie Xu

المصدر: European Journal of Cancer. 171:133-142

مصطلحات موضوعية: Cancer Research, Urinary Bladder Neoplasms, Oncology, Muscles, Biomarkers, Tumor, Tumor Microenvironment, Humans, Immunotherapy, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Immunohistochemistry, B7-H1 Antigen

الوصف: B7-H4, a sibling to PD-L1 in B7 family, has been reported to be a novel immune checkpoint that is prevalent among non-inflamed tumors. Herein, we attempt to explore the potential of B7-H4 in survival prediction and therapeutic guidance in muscle-invasive bladder cancer (MIBC) patients.This study included 391 patients from The Cancer Genome Atlas (TCGA) database and 122 patients from Zhongshan (ZS) Hospital. The evaluation of response to PD-L1 inhibitors was based on 270 patients in IMvigor210 cohort. Kaplan-Meier survival and multivariate analyses were performed to assess clinical outcomes in three cohorts. The correlation of B7-H4 expression with immune contexture and genomic alterations was analyzed based on immunohistochemistry, Microenvironment Cell Populations-counter (MCP-counter) tool, and whole-exome sequencing.MIBC patients with the high level of B7-H4 expression (B7-H4Despite adverse clinical outcomes, B7-H4

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f5b80c665d26202cc9ee9fba072350b2Test
https://doi.org/10.1016/j.ejca.2022.05.022Test

المؤلفون: Jingwen, Chi, Yicong, Liu, Lixia, Yang, Jianjun, Yang

المصدر: Journal of Oral and Maxillofacial Surgery. 80:1408-1423

مصطلحات موضوعية: Squamous Cell Carcinoma of Head and Neck, Macrophages, Programmed Cell Death 1 Receptor, Macrophage Activation, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Mice, Otorhinolaryngology, Cell Movement, Cell Line, Tumor, Animals, Humans, Mouth Neoplasms, Surgery, Gene Silencing, Oral Surgery, Cell Proliferation

الوصف: Tumor-associated macrophages can support oral squamous cell carcinoma (OSCC) progression, and overexpression of the immunomodulator B7H4 correlates with poor prognosis of OSCC patients. We performed this study to assess the effect of B7H4 silencing on macrophage polarization and explore the potential mechanism of B7H4 during OSCC progression.Short hairpin RNA targeting B7H4 was used to knock down B7H4. The predictor variable was B7H4 expression level, and the outcome variables were SCC9 cell growth and metastasis, M1/M2 macrophage ratio, and anti-programmed death-1 (PD-1)/STAT3 pathway-related protein levels. These were measured through real-time qPCR, Western blot analysis, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine assay, and transwell assay. In addition, a tumor xenograft mouse model was used to examine the effect of B7H4 silencing (+/- Colivelin, an activator of STAT3) on tumor growth and macrophage polarization.The expression of B7H4 in OSCC cell lines was more than 2-fold compared with that in human normal oral keratinocytes via real-time qPCR and Western blot analysis. Knockdown of B7H4 repressed the proliferation, migration, and invasion of SCC9 cells, which were detected by 5-ethynyl-2'-deoxyuridine and transwell assay, as well as reduced PD-1/STAT3 pathway-related protein levels, promoted M1 macrophage polarization, and inhibited M2 polarization. In vivo research demonstrated that B7H4 silencing also inhibited the growth of tumor xenograft and increased the M1/M2 ratio in an OSCC mouse model. Colivelin reversed the inhibitory effects of B7H4 knockdown on OSCC progression and reversed macrophage polarization both in vitro and in vivo.B7H4 is upregulated during OSCC progression. Its downregulation may promote M1 macrophage polarization and inhibit M2 macrophage polarization via deactivating the PD-1/STAT3 pathway, thus restraining OSCC development.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c04005f2a4c558302e82ec36055f38cTest
https://doi.org/10.1016/j.joms.2022.03.019Test

المؤلفون: Ramos, Paula S, Criswell, Lindsey A, Moser, Kathy L, Comeau, Mary E, Williams, Adrienne H, Pajewski, Nicholas M, Chung, Sharon A, Graham, Robert R, Zidovetzki, Raphael, Kelly, Jennifer A, Kaufman, Kenneth M, Jacob, Chaim O, Vyse, Timothy J, Tsao, Betty P, Kimberly, Robert P, Gaffney, Patrick M, Alarcón-Riquelme, Marta E, Harley, John B, Langefeld, Carl D, International Consortium on the Genetics of Systemic Erythematosus

المصدر: PLoS genetics. 7(12)

مصطلحات موضوعية: International Consortium on the Genetics of Systemic Erythematosus, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Receptors, Interleukin, Case-Control Studies, Cohort Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, OX40 Ligand, Interleukin-2 Receptor alpha Subunit, Genome-Wide Association Study, Genetic Pleiotropy, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Arthritis, Rheumatoid, Colitis, Ulcerative, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Receptors, Interleukin, Polymorphism, Single Nucleotide, Genetics, Developmental Biology

الوصف: In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0nk0g2w7Test

المؤلفون: Rees, Johanna

مصطلحات موضوعية: specific proteomic proximity labelling assay using tyramide, proteomics, B7-H4, microenvironment, integrins, HLA class I histocompatibility antigen α chain E, Breast Neoplasms, Cell Adhesion, Cell Line, Tumor, Cell Membrane, Cell Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Immune Checkpoint Inhibitors, Lymphocyte Activation, Protein Interaction Mapping, Protein Interaction Maps, Proteomics, T-Lymphocytes, Up-Regulation, V-Set Domain-Containing T-Cell Activation Inhibitor 1

الوصف: The immune checkpoint protein B7-H4 plays an important role in the positive as well as the negative regulation of immune T-cell responses. When expressed on cancer cells, B7-H4 inhibits T-cell activity, and numerous types of cancer cells use upregulation of B7-H4 as a survival strategy. Thus, B7-H4 is a potential target for anticancer drug therapy. Unfortunately, the cell biology of this molecule has yet to be fully elucidated. Even basic properties, such as the nature of B7-H4 interactors, are controversial. In particular, the cis-interactors of B7-H4 on cancer cell plasma membranes have not been investigated to date. The present study used a proteomic proximity-labelling assay to investigate the molecular neighbours of B7-H4 on the surface of the human breast cancer cells SK-BR-3. By comparison to a comprehensive proteome analysis of SK-BR-3 cells, the proximity method detected a relatively small number of low abundance plasma membrane proteins highly enriched for proteins known to modulate cell adhesion ...

الإتاحة: https://doi.org/10.17863/cam.48164Test
https://www.repository.cam.ac.uk/handle/1810/301087Test

المؤلفون: Hamilton, Erika, Spira, Alexander, Adams, Sylvia, Abuhadra, Nour, Giordano, Antonio, Parajuli, Ritesh, Han, Hyo, Weise, Amy, Marchesani, Aubri, Josephs, Kate, Chaudhry, Arvind

المصدر: Hematology/Oncology Meeting Abstracts

مصطلحات موضوعية: antibody drug conjugate, CD28 antigen, cell surface protein, endogenous compound, epidermal growth factor receptor 2, V set domain containing T cell activation inhibitor 1, adult, animal experiment, animal model, antineoplastic activity, breast cancer, cancer growth, cancer patient, cohort analysis, conference abstract, controlled study, disease control, drug efficacy, drug safety, endometrium cancer, female, health care quality, human, microtubule, nonhuman, ovary cancer, overall response rate, phase 1 clinical trial, preclinical study, retrospective study

الوصف: Objectives: Endometrial (EC) and ovarian cancers (OC) are some of the leading causes of cancer death among women. Despite therapeutic advances, many patients eventually develop resistance to available standard-of-care (SOC) therapies. B7-H4 is a poor prognostic factor and is overexpressed in several cancers, including endometrial, ovarian, and breast. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing antitumor immunity. XMT-1660 is a B7-H4-targeted Dolasynthen antibody drug conjugate (ADC) designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with a controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated antitumor activity in EC and OC PDX models. Methods: The phase I trial includes a first-in-human dose escalation (DES) portion followed by a dose expansion (EXP) evaluating XMT-1660 in patients with endometrial, ovarian, and breast cancers following progression on SOC. In the DES, BOIN (Bayesian Optimal Interval) design will be used to determine the MTD. The DES will assess the safety and preliminary efficacy and establish recommended phase II dose (RP2D). In the EXP portion, cohorts enrolling EC/OC, TNBC, ER+/HER2- BC are planned, and additional patients may be enrolled based on emerging data. The primary endpoints are safety and tolerability, overall response rate, disease control rate, and duration of response. Patients are not selected by B7-H4 status, but baseline tumor samples are collected for retrospective analysis. The trial is currently enrolling patients.

العلاقة: https://scholarlycommons.henryford.com/hematologyoncology_mtgabstracts/167Test; http://sfxhosted.exlibrisgroup.com/hfhs?sid=EMBASE&issn=10956859&id=doi:10.1016%2Fj.ygyno.2023.06.159&atitle=XMT-1660%3A+A+Phase+1b+trial+of+a+B7-H4+targeting+antibody+drug+conjugate+%28ADC%29+in+endometrial,+ovarian,+and+breast+cancers+%281250%29&stitle=Gynecol.+Oncol.&title=Gynecologic+Oncology&volume=176&issue=&spage=S158&epage=&aulast=Hamilton&aufirst=Erika&auinit=E.&aufull=Hamilton+E.&coden=&isbn=&pages=S158-&date=2023&auinit1=E&auinitmTest=

الإتاحة: https://scholarlycommons.henryford.com/hematologyoncology_mtgabstracts/167Test

المؤلفون: Zhou, Jie, Tian, Yuchen, Qu, Ying, Williams, Madyson, Yuan, Ye, Karvas, Rowan M, Sheridan, Megan A, Schulz, Laura C, Ezashi, Toshihiko, Roberts, Michael R, Schust, Danny J

مصطلحات موضوعية: Trophoblasts, Placenta, Humans, Premature Birth, Histocompatibility Antigens Class I, HLA Antigens, Cell Differentiation, Pregnancy, Infant, Newborn, Female, Embryonic Stem Cells, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Immune Checkpoint Proteins

الوصف: The placenta acts as a protective barrier to pathogens and other harmful substances present in the maternal circulation throughout pregnancy. Disruption of placental development can lead to complications of pregnancy such as preeclampsia, intrauterine growth retardation and preterm birth. In previous work, we have shown that expression of the immune checkpoint regulator, B7-H4/VTCN1, is increased upon differentiation of human embryonic stem cells (hESC) to an in vitro model of primitive trophoblast (TB), that VTCN1/B7-H4 is expressed in first trimester but not term human placenta and that primitive trophoblast may be uniquely susceptible to certain pathogens. Here we report on the role of VTCN1 in trophoblast lineage development and anti-viral responses and the effects of changes in these processes on major histocompatibility complex (MHC) class I expression and peripheral NK cell phenotypes.

وصف الملف: application/pdf

العلاقة: Frontiers in endocrinology; https://hdl.handle.net/10161/27899Test

الإتاحة: https://hdl.handle.net/10161/27899Test