521 Immune regulatory metabolites in human ovarian cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A557-A557
Author(s):  
Julian Lum ◽  
Marisa Kilgour ◽  
Sarah MacPherson ◽  
Lauren Zacharias ◽  
Sarah Keyes ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Serous Carcinoma ◽  
Learning Tools ◽  
Necrosis Factor Alpha ◽  
University Of British Columbia ◽  
Cytokine Tumor Necrosis Factor ◽  
Immunotherapy Target ◽  
The University

BackgroundImmune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Importantly, little is known about the heterogeneity of metabolites that are present or absent in specimens from human tumors and immune compartments.MethodsHere, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. We devised a stringent and robust protocol to enrich cell populations from surgically resected samples in patients with HGSC. We conducted mass spectrometry-based analysis and developed machine learning tools to highlight novel metabolites that are present in different cellular lineages of the tumor.ResultsCells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. T cells treated with MNA stimulated secretion of the tumor promoting cytokine tumor necrosis factor alpha.ConclusionsOur studies provide the first catalogue of metabolites in patient-derived tumors and T cells. We found that TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.Ethics ApprovalThis study was approved by the University of British Columbia and BC Cancer Research Ethics Board (H07-00463).ConsentWritten informed consent was obtained from the patient to use the results of this study for educational purposes including publications. A copy of the written consent is on file and available for review by the Editor of this journal.

scholarly journals 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

2021 ◽  
Vol 7 (4) ◽  
pp. eabe1174
Author(s):  
Marisa K. Kilgour ◽  
Sarah MacPherson ◽  
Lauren G. Zacharias ◽  
Abigail E. Ellis ◽  
Ryan D. Sheldon ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Serous Carcinoma ◽  
Necrosis Factor Alpha ◽  
Methyl Group ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Immunotherapy Target ◽  
Necrosis Factor

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.

scholarly journals 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

2020 ◽  
Author(s):  
Marisa K. Kilgour ◽  
Sarah MacPherson ◽  
Lauren Zacharias ◽  
Sarah Keyes ◽  
Brenna Pauly ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Mitochondrial Activity ◽  
Necrosis Factor Alpha ◽  
Cd8 Cells

ABSTRACTImmune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few notable exceptions, their identities remain largely unknown. We uncovered the immune regulatory metabolic states and metabolomes of sorted tumor and stromal, CD4+, and CD8+ cells from the tumor and ascites of patients with high-grade serous ovarian cancer (HGSC) using high-dimensional flow cytometry and metabolomics supplemented with single cell RNA sequencing. Flow cytometry revealed that tumor cells show a consistently greater uptake of glucose than T cells, but similar mitochondrial activity. Cells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the gene encoding the enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Treatment of T cells with MNA resulted in an increase in T cell-mediated secretion of the tumor promoting cytokine tumor necrosis factor alpha. Thus, the TME-derived metabolite MNA contributes to an alternative and non-cell autonomous mechanism of immune modulation of T cells in HGSC. Collectively, uncovering the tumor-T cell metabolome may reveal metabolic vulnerabilities that can be exploited using T cell-based immunotherapies to treat human cancer.

scholarly journals Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Matthew Luzentales-Simpson ◽  
Yvonne C. F. Pang ◽  
Ada Zhang ◽  
James A. Sousa ◽  
Laura M. Sly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Bowel Diseases ◽  
Necrosis Factor Alpha ◽  
Cell Recruitment ◽  
Inflammatory Monocytes ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Cytokine Tumor Necrosis Factor ◽  
Inflammatory Bowel

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.

Mobile Clinical Learning Tools Using Networked Personal Digital Assistants (PDAs)

2009 ◽  
pp. 1256-1260
Author(s):  
Bernard Mark Garrett
Keyword(s):  
Nursing Students ◽  
Personal Digital Assistants ◽  
Clinical Learning ◽  
Learning Tools ◽  
Community Settings ◽  
Clinical Experiences ◽  
School Of Nursing ◽  
University Of British Columbia ◽  
Complex Process ◽  
The University

The School of Nursing at the University of British Columbia has more than 300 nursing students engaged in supervised clinical practice in hospital and community settings around Vancouver. Likewise, the Faculty of Medicine has more than 200 medical students undertaking supervised clinical experience locally and remotely in the Prince George and Vancouver Island regions. The management of these clinical experiences and the promotion of learning while in an active clinical setting is a complex process.

Mobile Clinical Learning Tools Using Networked Personal Digital Assistants (PDAs)

2011 ◽  
pp. 836-840
Author(s):  
Bernard Mark Garrett
Keyword(s):  
Nursing Students ◽  
Personal Digital Assistants ◽  
Clinical Learning ◽  
Learning Tools ◽  
Community Settings ◽  
Clinical Experiences ◽  
School Of Nursing ◽  
University Of British Columbia ◽  
Complex Process ◽  
The University

The School of Nursing at the University of British Columbia has more than 300 nursing students engaged in supervised clinical practice in hospital and community settings around Vancouver. Likewise, the Faculty of Medicine has more than 200 medical students undertaking supervised clinical experience locally and remotely in the Prince George and Vancouver Island regions. The management of these clinical experiences and the promotion of learning while in an active clinical setting is a complex process.

Mobile Clinical Learning Tools Using Networked Personal Digital Assistants (PDAs)

2006 ◽  
pp. 404-407
Author(s):  
Bernard Mark Garrett
Keyword(s):  
Nursing Students ◽  
Personal Digital Assistants ◽  
Clinical Learning ◽  
Learning Tools ◽  
Community Settings ◽  
Clinical Experiences ◽  
School Of Nursing ◽  
University Of British Columbia ◽  
Complex Process ◽  
The University

The School of Nursing at the University of British Columbia has more than 300 nursing students engaged in supervised clinical practice in hospital and community settings around Vancouver. Likewise, the Faculty of Medicine has more than 200 medical students undertaking supervised clinical experience locally and remotely in the Prince George and Vancouver Island regions. The management of these clinical experiences and the promotion of learning while in an active clinical setting is a complex process.

Bioinformatics Analysis Identifies CPZ as a Tumor Immunology Biomarker For Gastric Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Yuan Gu ◽  
Ying Gao ◽  
Xiaodan Tang ◽  
Huizhong Xia ◽  
Kunhe Shi
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Tumor Immunology ◽  
Bioinformatics Analysis ◽  
Human Cancer ◽  
Disease Free Survival ◽  
Kaplan Meier ◽  
Potential Biomarker ◽  
Pathway Regulation

Background: Gastric cancer (GC) is one of the most common malignancies worldwide. However, the biomarkers for the prognosis and diagnosis of Gastric cancer were still need. Objective: The present study aimed to evaluate whether CPZ could be a potential biomarker for GC. Method: Kaplan-Meier plotter (http://kmplot.com/analysis/) was used to determine the correlation between CPZ expression and overall survival (OS) and disease-free survival (DFS) time in GC [9]. We analyzed CPZ expression in different types of cancer and the correlation of CPZ expression with the abundance of immune infiltrates, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, via gene modules using TIMER Database. Results: The present study identified that CPZ was overexpressed in multiple types of human cancer, including Gastric cancer. We found that overexpression of CPZ correlates to the poor prognosis of patients with STAD. Furthermore, our analyses show that immune infiltration levels and diverse immune marker sets are correlated with levels of CPZ expression in STAD. Bioinformatics analysis revealed that CPZ was involved in regulating multiple pathways, including PI3K-Akt signaling pathway, cGMP-PKG signaling pathway, Rap1 signaling pathway, TGF-beta signaling pathway, regulation of cell adhesion, extracellular matrix organization, collagen fibril organization, collagen catabolic process. Conclusion: This study for the first time provides useful information to understand the potential roles of CPZ in tumor immunology and validate it to be a potential biomarker for GC.

scholarly journals Evaluation and Lessons Learned from a Campus as a Living Lab Program to Promote Sustainable Practices

2021 ◽  
Vol 13 (4) ◽  
pp. 1739
Author(s):  
Paul Save ◽  
Belgin Terim Cavka ◽  
Thomas Froese
Keyword(s):  
Learning Curve ◽  
Business Process ◽  
Lessons Learned ◽  
Process Models ◽  
Sustainable Practices ◽  
Business Process Models ◽  
District Energy ◽  
University Of British Columbia ◽  
Living Lab ◽  
The University

Any group that creates challenging goals also requires a strategy to achieve them and a process to review and improve this strategy over time. The University of British Columbia (UBC) set ambitious campus sustainability goals, including a reduction in its greenhouse gas emissions to 33% below the 2007 level by 2015, and 100% by 2050 (UBC, 2006). The University pursued these goals through a number of specific projects (such as major district energy upgrade and a bioenergy facility) and, more generally, through a “Campus as a Living Lab” (CLL) initiative to marry industry, campus operations, and research to drive innovative solutions. The CLL program has achieved significant successes while also demonstrating many opportunities for improvements and lessons learned. The aim of this study was to examine the UBC CLL program, to identify and formalize its operations, to extract key transferable characteristics, and to propose replicable processes that other universities and municipalities can follow to expand their sustainable practices in similar ways. There was a learning curve with implementing a CLL program at UBC; thus, the goal of this study was to potentially shorten this learning curve for others. The research involved an ethnographic approach in which researchers participated in the CLL process, conducted qualitative analysis, and captured the processes through a series of business process models. The research findings are shared in two parts: 1. generalized lessons learned through key transferrable characteristics; 2. a series of generic organizational charts and business process models (BPMs) culminated with learned strategies through defined processes that illustrate what was required to create a CLL program at UBC. A generalized future improvement plan for UBC CLL programs is defined, generic BPMs about CLL projects are evaluated, and the level of engagement of multiple stakeholders through phases of project life cycle given in the conclusion for future use of other Living Lab organizations.

scholarly journals Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma

2021 ◽  
Author(s):  
Rosanna L. Wustrack ◽  
Evans Shao ◽  
Joey Sheridan ◽  
Melissa Zimel ◽  
Soo-Jin Cho ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Tumor Size ◽  
Immune Cell ◽  
Human Cancer ◽  
Soft Tissue Sarcomas ◽  
Inverse Correlation ◽  
Anatomical Location ◽  
Pleomorphic Sarcoma

Abstract Background Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. Methods Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. Results We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. Conclusions Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

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