The role of amino acid metabolism in the regulation of T cell fate

The study of the metabolism of the immune system is a rapidly advancing field. It is highly dynamic, and changes rapidly upon activation, and although both innate and adaptive cells undergo activation-induced metabolic changes, the changes that are associated with T cell activation have been extensively studied. Early work has identified a rapid increase in the uptake and use of glucose following T cell activation, and glycolysis followed by export of lactate, rather than TCA cycle metabolism, a phenomenon known as aerobic glycolysis. While this glycolytic phenotype has received a great deal of attention, it is accompanied by corresponding increases in amino acid metabolism. Glutamine is a non-essential amino acid which is taken up following activation to help replenish the TCA cycle during aerobic glycolysis, and leucine in an essential amino acid which is required for activation of mTOR signaling. While metabolic alterations following T cell activation were once seen as secondary to the needs of an activated cell, it is becoming increasingly clear that metabolism has a powerful ability to shape and direct the immune response. As certain patterns of metabolism have been associated with particular T cell fates, such as the previously described aerobic glycolysis in activated effector cells, or the increased reliance on oxidative metabolism on long-lived memory cells, we hypothesized that it might be possible to alter T cell immune responses by altering their use of metabolites, and particularly their use of the amino acids glutamine and leucine. First, we assessed the role of glutamine metabolism in CD4 T cell responses. Previous research has demonstrated that the presence of glutamine in T cell culture is essential for proliferation. We recapitulated these findings, and extended them into a model of CD4 T cell polarization in which glutamine was shown to be dispensable for Th1 skewing, while essential for the development of Th2 cells in vitro. This was demonstrated to be due to a specific requirement for glutamine in increasing the epigenetic accessibility of the Th2 cytokine locus, which is required for the transcription and translation of IL4 and IL13. The role of glutamine in Th2 cell development was further explored in vivo in a house dust mite induced asthma model, in which pharmacologic inhibition of glutamine metabolism was shown to reduce not just Th2 T cell formation, but also ILC2 and M2 macrophage polarization, while not affecting M1 macrophages or regulatory T cells, illustrating the selective effect of glutamine metabolism. Next, glutamine metabolism was assessed in CD8 T cell memory formation. As previously stated, memory cells rely on a more oxidative metabolism than effector cells. By restricting glutamine in vitro in cultured CD8 T cells, we decreased the proliferation of those cells, but saw a striking change in their phenotype, reflecting a long-lived central memory-like cell. When these cells were adoptively transferred and stimulated, they were able to persist better in circulation than CD8 T cells cultured in standard media, and were better able to mount a polyfunctional cytokine response upon re-challenge. These cells also were able to mount a more vigorous anti-tumor response upon adoptive cellular therapy in an implantable tumor model. Interestingly, the only perturbation these cells were submitted to was a short-term culture in restricted glutamine media, and this was sufficient to dramatically alter their response for weeks to come, demonstrating the powerful role metabolism plays in governing the T cell response. Lastly, we explored the role of the amino acid leucine both in vitro and in vivo. Restriction of leucine metabolism in vitro in CD4 T cells selectively affected Th1 cell skewing, decreasing the numbers of these cells and inducing ectopic expression of IL4 and IL13. An in vivo profiling of leucine transporter LAT1 expression in conditions of activation indicated that its expression is increased on activated immune cells and especially T cells in activation in viral and transplant systems, and the selective LAT1-specific depletion of cells is an effective strategy for the elimination of activated T cells in both viral and transplant models. This work on both glutamine and leucine indicates the role that metabolism plays in shaping the immune response, and demonstrates that by modulating metabolism we can powerfully alter how an immune response is mounted, beyond simply turning it on or off, but by exquisitely altering the balance between Th1 and Th2, or effector and memory, in order to promote the exact response required for a particular situation

Androgen Receptor Inhibition Suppresses Anti-Tumor Neutrophil Response Against Bone Metastatic Prostate Cancer via Regulation of TβRI Expression

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that PCa progression dictates PMN cell surface markers and gene expression, but not cytotoxicity against PCa. Importantly, we also identified a novel phenomenon in which second generation androgen deprivation therapy (ADT) suppresses PMN cytotoxicity via increased transforming growth factor beta receptor I (TβRI). High dose testosterone and genetic or pharmacologic TβRI inhibition rescued androgen receptor-mediated neutrophil suppression and restored neutrophil anti-tumor immune response. These studies highlight the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa

Microphysiologic Human Tissue Constructs Reproduce Autologous Age-Specific BCG and HBV Primary Immunization <i>in vitro</i>

Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide, and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitial interphase, suitable for pre-clinical modeling of distinct age-targeted immunity in vitro. Our Tissue Constructs (TCs) enable autonomous extravasation of monocytes that undergo rapid self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and licensed vaccines such as Bacille Calmette-Guérin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat-treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Vaccine-pulsed TCs autonomously generated DCs that induced single-antigen recall responses from autologous naïve and memory CD4+ T lymphocytes, matching study participant immune-status, including BCG responses paralleling donor PPD status, BCG-induced adenosine deaminase (ADA) activity paralleling infant cohorts in vivo, and multi-dose HBV antigen-specific responses as demonstrated by lymphoproliferation and TCR sequencing. Overall, our microphysiologic culture method reproduced age- and antigen-specific recall responses to BCG and HBV immunization, closely resembling those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre-clinical selection of effective age-targeted vaccine candidates.</p

Microphysiologic Human Tissue Constructs Reproduce Autologous Age-Specific BCG and HBV Primary Immunization in vitro

Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide, and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitial interphase, suitable for pre-clinical modeling of distinct age-targeted immunity in vitro. Our Tissue Constructs (TCs) enable autonomous extravasation of monocytes that undergo rapid self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and licensed vaccines such as Bacille Calmette-Guérin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat-treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Vaccine-pulsed TCs autonomously generated DCs that induced single-antigen recall responses from autologous naïve and memory CD4+ T lymphocytes, matching study participant immune-status, including BCG responses paralleling donor PPD status, BCG-induced adenosine deaminase (ADA) activity paralleling infant cohorts in vivo, and multi-dose HBV antigen-specific responses as demonstrated by lymphoproliferation and TCR sequencing. Overall, our microphysiologic culture method reproduced age- and antigen-specific recall responses to BCG and HBV immunization, closely resembling those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre-clinical selection of effective age-targeted vaccine candidates

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

What is known about the role of rural-urban residency in relation to self-management in people affected by cancer who have completed primary treatment? A scoping review.

Purpose Despite wide acknowledgement of differences in levels of support and health outcomes between urban and rural areas there is a lack of research that explicitly examines these differences in relation to self-management in people affected by cancer following treatment. This scoping review aimed to map the existing literature that examines self-management in people affected by cancer who were post-treatment from rural and urban areas. Methods Arksey and O’Malley’s framework for conducting a scoping review was utilised. Keyword searches were performed in: Academic Search Complete, CINAHL, MEDLINE, PsycINFO, Scopus and Web of Science. Supplementary searching activities were also conducted. Results 438 articles were initially retrieved and 249 duplicates removed leaving 192 articles that were screened by title, abstract and full text. 9 met the eligibility criteria and were included in the review. They were published from 2011-2018 and conducted in the USA (n=6), Australia (n=2) and Canada (n=1). None of the studies offered insight into self-managing cancer within a rural-urban context in the UK. Studies used qualitative (n=4), mixed methods (n=4) and quantitative designs (n=1). Conclusion If rural and urban populations define their health in different ways as some of the extant literature suggests then efforts to support self-management in both populations will need to be better informed by robust evidence given the increasing focus on patient centred care. It is important to consider if residency can be a predictor of as well as, a barrier or facilitator to self-management

Psychosocial service use: a qualitative exploration from the perspective of rural Australian cancer patients

PurposeThis study aims to identify key issues associated with the provision of psychosocial care from the perspective of rural Australian cancer patients and determine culturally appropriate methods that may reduce barriers to service use.MethodSeventeen purposively sampled adult South Australians who lived outside metropolitan Adelaide, had a diagnosis of cancer and various demographic and medical histories participated in semi-structured, face-to-face interviews. Participants also completed a demographic questionnaire. Qualitative data were analysed using thematic analysis.ResultsFive key themes were identified: (1) psychosocial support is highly valued by those who have accessed it, (2) having access to both lay and professional psychosocial support is vitally important, (3) accessing psychosocial services is made difficult by several barriers (lack of information about services, initial beliefs they are unnecessary, feeling overwhelmed and concerns about stigma and dual relationships), (4) medical staff located in metropolitan treatment centres are not sufficiently aware of the unique needs of rural patients and (5) patients require better access to psychosocial services post-treatment. Methods through which rural patients believe access to psychosocial services could be improved include: (1) providing more rural-specific information on psychosocial care, (2) improving communication between health care providers and referral to psychosocial services and (3) making psychosocial services a standard part of care.ConclusionsRural cancer patients want their unique needs to be recognised and to be treated differently to their urban counterparts. There is a need for more targeted and rurally relevant information for rural cancer patients, both to inform them of, and change their attitudes towards, psychosocial services. Other practical recommendations are also discussed.Kate Gunn, Deborah Turnbull, J. Lindsay McWha, Matthew Davies, Ian Olve