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  • 1
    Online Resource
    Online Resource
    T cell expressed microRNA-155 promotes antitumor immunity and immune checkpoint blockade responses in colon cancer through repression of Ship1
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 172.13-172.13
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 172.13-172.13
    Abstract: Colorectal cancer (CRC) is the 2 nddeadliest cancer globally and has the 3 rdhighest incidence and mortality in the United States. Advanced-stage disease is incurable by current clinical standards. Thus, alternative treatments are being explored, including immune checkpoint blockade (ICB) to prevent T cell inactivation by tumors. ICB induces a robust response in patients with microsatellite instability-high (MSI-H) metastatic CRC. However, most CRC patients are not responsive to ICB. Our analysis revealed MSI-H patients exhibit an immune cell-mediated inflammatory tumor microenvironment (TME) that is associated with the expression of microRNAs (miRs) linked to immune cell regulation. By studying T cell-associated miRs in MSI-H colon cancer patients, and through Crispr-Cas9 based in vivo screening, we identified T cell miR-155 as the miR most highly associated with ICB responsive patients. T cell miR-155 was necessary for ICB responses in multiple colon cancer preclinical models and promoted Th1-helper T cell and cytotoxic T lymphocyte enrichment in the TME, reflecting a robust immune response. T cell miR-155 controls ICB response and cancer immunity by repressing a network of target genes, most notably SHIP1. Loss of T cell miR-155 derepressed SHIP-1 gene expression in our study. Additionally, SHIP-1 was expressed in human tumor-associated T cells, with lower expression correlating to better patient outcomes. In vivo, we demonstrated that SHIP-1 inhibition partially restored tumor immunity in mice specifically lacking T cell miR-155. These findings suggest a dependence on T cell miR-155 and its targets for effective cancer immunity and ICB efficacy in colon cancer, identifying miR-155 as a candidate biomarker and therapeutic. Supported by grants from NIH (F30 CA260977)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.172.13
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Diet-induced weight loss restores T cell number and function in the intestinal epithelium of obese mice
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 215.10-215.10
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 215.10-215.10
    Abstract: Over 30% of adults have a BMI greater than 30 in the United States. Obesity is associated with complications such as type 2 diabetes and chronic non-healing wounds. Our laboratory has demonstrated that obesity and type 2 diabetes negatively impact T cell number, proliferation and cytokine production in the epithelial layer of the skin and the intestine. However, little is known about whether the number and function of these T cells can be restored to normal levels. Here we investigated whether diet-induced weight loss would restore T cells in the small intestine of obese mice. Mice were placed on either 10% kcal Normal Chow Diet (NCD) for 14 weeks, 60% kcal high fat diet (HFD) for 14 weeks, or 60% kcal HFD for 7 weeks followed by a 10% kcal diet for the remaining 7 weeks. The small intestine was examined by snap freezing the tissue, cutting 5um sections, staining the tissue sections for T cells, and examining the sections by immunofluorescent microscopy. Diet-induced weight loss restored T cell numbers to their original levels in the small intestine. In addition, short-term dieting restored the expression of adhesion molecules such as CD103 and chemokine receptors such as CCR9 on the IEL. Previously we have shown that obese mice are more sensitive to DSS-induced colitis. Diet-induced weight loss rescued mice from excessive bleeding and weight loss due to DSS-induced damage. Together this data suggests that while obesity impairs lymphocytes in barrier tissues such as the intestinal epithelium, diet-induced weight loss can restore T cell number and improve the outcome from colitis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.215.10
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations
    American Society for Clinical Investigation ; 2017
    In:  Journal of Clinical Investigation Vol. 127, No. 3 ( 2017-2-13), p. 982-986
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 127, No. 3 ( 2017-2-13), p. 982-986
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    URL: Article
    DOI: 10.1172/JCI91161
    DOI: 10.1172/JCI91161DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2017
    detail.hit.zdb_id: 2018375-6
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  • 4
    Online Resource
    Online Resource
    miR-aculous new avenues for cancer immunotherapy
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-9-28)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-9-28)
    Abstract: The rising toll of cancer globally necessitates ingenuity in early detection and therapy. In the last decade, the utilization of immune signatures and immune-based therapies has made significant progress in the clinic; however, clinical standards leave many current and future patients without options. Non-coding RNAs, specifically microRNAs, have been explored in pre-clinical contexts with tremendous success. MicroRNAs play indispensable roles in programming the interactions between immune and cancer cells, many of which are current or potential immunotherapy targets. MicroRNAs mechanistically control a network of target genes that can alter immune and cancer cell biology. These insights provide us with opportunities and tools that may complement and improve immunotherapies. In this review, we discuss immune and cancer cell–derived miRNAs that regulate cancer immunity and examine miRNAs as an integral part of cancer diagnosis, classification, and therapy.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2022.929677
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 5
    Online Resource
    Online Resource
    Presentation1.pptx
    Frontiers Media SA ; 2023
    In:  Frontiers in Genetics Vol. 14 ( 2023-5-9)
    Details
    In: Frontiers in Genetics, Frontiers Media SA, Vol. 14 ( 2023-5-9)
    Abstract: Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fgene.2023.1192799
    DOI: 10.3389/fgene.2023.1192799.s001
    DOI: 10.3389/fgene.2023.1192799.s002
    DOI: 10.3389/fgene.2023.1192799.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606823-0
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  • 6
    Online Resource
    Online Resource
    GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 617, No. 7962 ( 2023-05-25), p. 764-768
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 617, No. 7962 ( 2023-05-25), p. 764-768
    Abstract: Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06034-3
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 7
    Online Resource
    Online Resource
    Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 619, No. 7971 ( 2023-07-27), p. E61-E61
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 619, No. 7971 ( 2023-07-27), p. E61-E61
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06383-z
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 8
    Online Resource
    Online Resource
    Obesity Modulates Intestinal Intraepithelial T Cell Persistence, CD103 and CCR9 Expression, and Outcome in Dextran Sulfate Sodium–Induced Colitis
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 203, No. 12 ( 2019-12-15), p. 3427-3435
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 203, No. 12 ( 2019-12-15), p. 3427-3435
    Abstract: Obesity impacts over 30% of the United States population, resulting in a wide array of complications. Included among these is the deterioration of the intestinal barrier, which has been implicated in type 2 diabetes and susceptibility to bacterial transepithelial migration. The intestinal epithelium is maintained by αβ and γδ intraepithelial T lymphocytes, which migrate along the epithelia, support epithelial homeostasis, and protect from infection. In this study, we investigate how obesity impacts intraepithelial lymphocyte (IEL) persistence and function in intestinal homeostasis and repair. Mice were fed a high-fat diet to induce obesity and to study immunomodulation in the intestine. There is a striking reduction in αβ and γδ IEL persistence as obesity progresses with a different mechanism in αβ versus γδ IEL populations. CD4+ and CD4+CD8+ αβ intraepithelial T lymphocytes exhibit reduced homeostatic proliferation in obesity, whereas both αβ and γδ IELs downregulate CD103 and CCR9. The reduction in intraepithelial T lymphocytes occurs within 7 wk of high-fat diet administration and is not dependent on chronic inflammation via TNF-α. Young mice administered a high-fat diet upon weaning exhibit the most dramatic phenotype, showing that childhood obesity has consequences on intestinal IEL seeding. Together, this dysfunction in the intestinal epithelium renders obese mice more susceptible to dextran sulfate sodium–induced colitis. Diet-induced weight loss restores IEL number and CD103/CCR9 expression and improves outcome in colitis. Together, these data confirm that obesity has immunomodulatory consequences in intestinal tissues that can be improved with weight loss.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1900082
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 9
    Online Resource
    Online Resource
    Role of TNF-α reception in epidermal γδ T cell function during homeostasis and after TCR stimulation
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 47.9-47.9
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 47.9-47.9
    Abstract: Inflammatory responses mediated by the cellular components of epithelial tissues are essential to the wound healing process. Epidermal γδ T cells, also known as dendritic epidermal T cells (DETC), play key roles in the wound healing process by producing growth factors, chemokines and cytokines necessary for the proliferation and migration of epithelial cells. DETC activation occurs via the γδ TCR, however, second and third signals are required to sustain the activation and production of factors needed in functions such as wound repair. While progress has been made on elucidating signal 2 costimulatory signals such as JAML and CAR, less is understood about what signals are required for signal 3 in DETC and what roles TNF-α plays in regulating and sustaining DETC function. TNF-α signals through two receptors, tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2). These receptors elicit varied responses that include apoptosis, survival or inflammation. Our data indicate that DETC upregulate type 1 chemokines and their corresponding chemokine receptor expression during inflammation. We have also found that a subset of DETC express TNFR1 and TNFR2 on their cell surface constitutively suggesting a requirement for tonic TNFR signaling for particular DETC populations. We have quantified chemokine, cytokine and growth factor production from DETC stimulated in the presence or absence of TNF-α using Luminex technology. Additionally, we have investigated which TNFR is responsible for modulating DETC function by comparing DETC function in cells isolated from wild-type, TNFR1 and/or 2 knockout mice. Identifying which factors regulate DETC function and activation could provide potential targets for improving DETC function in wound repair.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.47.9
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 10
    Online Resource
    Online Resource
    A Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-05-11)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-05-11)
    Abstract: Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt , termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-22923-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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