Potential role of MAIT cells in cancer immunotherapy and viral infection

Mucosa-associated invariant T (MAIT) cells are an unconventional T cell subset with specialized antimicrobial functions. In humans, MAIT cells are characterized by their effector memory phenotype, rapid cytolytic capacity, and tissue-homing properties. Given their natural enrichment in the liver and mucosal barrier tissues, this thesis aimed to explore the potential of redirecting MAIT cells for hepatitis virus-related liver cancer immunotherapy using MHC class-I restricted T cell receptors (TCRs). Additionally, we sought to explore the role of MAIT cells in the context of another front-line immune tissue, the female genital mucosa, in human immunodeficiency virus type 1 (HIV-1) infection. In paper I, a MAIT cell expansion methodology was developed to generate clinically relevant quantities of human MAIT cells for immunotherapies. The MAIT cell expansion protocol was highly reproducible and resulted in MAIT cell cultures with an activated phenotype, enhanced cytolytic potential, and improved tissue homing capacity. These features make them particularly suitable for solid tumour-targeting. We tested this hypothesis in paper II, by engineering expanded MAIT cells to express a TCR with specificity for hepatitis B virus (HBV). Using 2D and 3D hepatoma cell models of HBV-related hepatocellular carcinoma, we compared the antiviral, cytotoxic, and tumour homing properties of the TCR-redirected MAIT cells with those of conventional T cells currently being used in the clinic. We demonstrated that the MAIT cells not only acquired a distinct polyfunctional antigen-specific profile in response to HBV, but also retained their antimicrobial properties, and readily migrated towards the tumor targets in a 3D microfluidic model. In paper III, we investigated the phenotype of MAIT cells in women living with chronic HIV-1 infection. We initially confirmed that circulating MAIT cells were activated and numerically depleted in the blood. However, MAIT cells were preserved in the cervical mucosa. The TRAV1-2-TRAJ20 MAIT TCR transcript was highly expressed in the ectocervix and was significantly upregulated in the HIV-1 infected women relative to uninfected controls. This indicates that MAIT cells may be poised to recognize stimuli unique to that environment, and that HIV-1 infection may shape the MAIT cell population in the female genital tract. In summary, the research covered by this thesis demonstrates the potential role of MAIT cells in the context of virus-related cancer immunotherapy and barrier tissue infiltration. Taken together, these findings illuminate new avenues of research in MAIT cell biology in human health and disease

Exploring Community-Based Nutrition Education Programs on Children’s Knowledge of Effective Budgeting and Nutritional Analysis

Children from low-income areas, ages 5-18, are at high risk for obesity and other related nutritional issues, partially due to lack of knowledge about effective budgeting and nutritional content analysis. Little information is known about the education provided by current community programs in Hampton Roads for teaching children to 1) shop smart, 2) read nutrition labels, and 3) the importance of eating healthier. We propose a longitudinal (12-week) observational study to determine what community-based education is provided to children on how and why to shop smart and read nutritional content; and to determine whether or not the education is effective. The data will be collected via researcher-developed questionnaires on nutritional education and attendance at community programs, then analyzed using the Pearson’s product-moment correlation technique

Effects of Repeated Sublethal External Exposure to Deep Water Horizon Oil on the Avian Metabolome

We assessed adverse effects of external sublethal exposure of Deepwater Horizon, Mississippi Canyon 252 oil on plasma and liver metabolome profiles of the double-crested cormorant (Phalacrocorax auritus), a large (1.5 to 3.0 kg) diving waterbird common in the Gulf of Mexico. Metabolomics analysis of avian plasma showed significant negative effects on avian metabolic profiles, in some cases after only two external exposures (26 g cumulative) to oil. We observed significant (p \u3c 0.05) changes in intermediate metabolites of energy metabolism and fatty acid and amino acid metabolic pathways in cormorants after repeated exposure to oil. Exposure to oil increased several metabolites (glycine, betaine, serine and methionine) that are essential to the one-carbon metabolism pathway. Lipid metabolism was affected, causing an increase in production of ketone bodies, suggesting lipids were used as an alternative energy source for energy production in oil exposed birds. In addition, metabolites associated with hepatic bile acid metabolism were affected by oil exposure which was correlated with changes observed in bile acids in exposed birds. These changes at the most basic level of phenotypic expression caused by sublethal exposure to oil can have effects that would be detrimental to reproduction, migration, and survival in avian species

Prevalence of Parvovirus B19 Viremia Among German Blood Donations and the Relationship to ABO and Rhesus Blood Group Antigens

Background Asymptomatic blood donors can transmit human parvovirus B19 (B19V). Methods We assessed the B19V prevalence among a large cohort of blood donations collected in Germany during 2015–2018. Results In total, 167 123 donations were screened for B19V deoxyribonucleic acid with 22 cases of viremia identified (0.013% positive). Infections peaked at a 4-year interval and the highest number of cases occurred in the summer months. All 22 infections were found in rhesus D-antigen-positive donations, suggesting a protective factor in donors who lack this antigen. Conclusions These findings contribute to our understanding of risk factors for B19V infection among central European blood and plasma donors

Human MAIT cells endowed with HBV specificity are cytotoxic and migrate towards HBV-HCC while retaining antimicrobial functions

Background & Aims: Virus-specific T cell dysfunction is a common feature of HBV-related hepatocellular carcinoma (HBV-HCC). Conventional T (ConT) cells can be redirected towards viral antigens in HBV-HCC when they express an HBV-specific receptor; however, their efficacy can be impaired by liver-specific physical and metabolic features. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the liver and can elicit potent intrahepatic effector functions. Here, we engineered ConT and MAIT cells to kill HBV expressing hepatoma cells and compared their functional properties. Methods: Donor-matched ConT and MAIT cells were engineered to express an HBV-specific T cell receptor (TCR). Cytotoxicity and hepatocyte homing potential were investigated using flow cytometry, real-time killing assays, and confocal microscopy in 2D and 3D HBV-HCC cell models. Major histocompatibility complex (MHC) class I-related molecule (MR1)-dependent and MR1-independent activation was evaluated in an Escherichia coli THP-1 cell model and by IL-12/IL-18 stimulation, respectively. Results: HBV TCR-MAIT cells demonstrated polyfunctional properties (CD107a, interferon [IFN] γ, tumour necrosis factor [TNF], and IL-17A) with strong HBV target sensitivity and liver-homing chemokine receptor expression when compared with HBV TCR-ConT cells. TCR-mediated lysis of hepatoma cells was comparable between the cell types and augmented in the presence of inflammation. Coculturing with HBV+ target cells in a 3D microdevice mimicking aspects of the liver microenvironment demonstrated that TCR-MAIT cells migrate readily towards hepatoma targets. Expression of an ectopic TCR did not affect the ability of the MAIT cells to be activated via MR1-presented bacterial antigens or IL-12/IL-18 stimulation. Conclusions: HBV TCR-MAIT cells demonstrate anti-HBV functions without losing their endogenous antimicrobial mechanisms or hepatotropic features. Our results support future exploitations of MAIT cells for liver-directed immunotherapies. Lay summary: Chronic HBV infection is a leading cause of liver cancer. T cell receptor (TCR)-engineered T cells are patients’ immune cells that have been modified to recognise virus-infected and/or cancer cells. Herein, we evaluated whether mucosal-associated invariant T cells, a large population of unconventional T cells in the liver, could recognise and kill HBV infected hepatocytes when engineered with an HBV-specific TCR. We show that their effector functions may exceed those of conventional T cells currently used in the clinic, including antimicrobial properties and chemokine receptor profiles better suited for targeting liver tumours

Experimental and modeled thermoregulatory costs of repeated sublethal oil exposure in the Double-crested Cormorant, \u3ci\u3ePhalacrocorax auritus\u3c/i\u3e

To fully understand the impact of oil exposure, it is important to understand sublethal effects like how increased thermoregulatory costs may affect survival and reproduction. However, it is difficult and time-consuming to measure these effects in wild animals. We present a novel use of a bioenergetics model, Niche Mapper™, to estimate thermoregulatory impacts of oiling, using data from captive Double-crested Cormorants (Phalacrocorax auritus) experimentally exposed to oil. Oiled cormorants had significant increases in surface body temperatures following exposure. Niche Mapper accurately predicted surface temperatures and metabolic rates for unoiled and oiled cormorants and predicted 13–18% increased daily energetic demands due to increased thermoregulatory costs of oiling, consistent with increased food consumption observed in experimentally oiled cormorants. We show that Niche Mapper can provide valuable insight into sublethal oiling effects by quantifying the extent to which thermoregulatory costs divert energy resources away from important life processes like maintenance, reproduction and migration

The People's Trial : supporting the public's understanding of randomised trials

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Simone Lepage, Aoife O’Shaughnessy, and Louise Foley for their support with the research project. We would also like to thank Rob & Paul Digital Design™, Galway, Ireland. In addition, we would like to thank Marina Zaki for her support of The People’s Trial, in particular her expertise in promoting The People’s Trial through social media channels. Funding This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award (grant reference KEDS-2018-012) 2018. The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD

Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies

The application of monoclonal antibodies (mAbs) for the treatment of melanoma has significantly improved the clinical management of this malignancy over the last decade. Currently approved mAbs for melanoma enhance T cell effector immune responses by blocking immune checkpoint molecules PD-L1/PD-1 and CTLA-4. However, more than half of patients do not benefit from treatment. Targeting the prominent myeloid compartment within the tumor microenvironment, and in particular the ever-abundant tumor-associated macrophages (TAMs), may be a promising strategy to complement existing therapies and enhance treatment success. TAMs are a highly diverse and plastic subset of cells whose pro-tumor properties can support melanoma growth, angiogenesis and invasion. Understanding of their diversity, plasticity and multifaceted roles in cancer forms the basis for new promising TAM-centered treatment strategies. There are multiple mechanisms by which macrophages can be targeted with antibodies in a therapeutic setting, including by depletion, inhibition of specific pro-tumor properties, differential polarization to pro-inflammatory states and enhancement of antitumor immune functions. Here, we discuss TAMs in melanoma, their interactions with checkpoint inhibitor antibodies and emerging mAbs targeting different aspects of TAM biology and their potential to be translated to the clinic

Does reading a book in bed make a difference to sleep in comparison to not reading a book in bed? : The People's Trial- an online, pragmatic, randomised trial

Acknowledgements The People’s Trial team members acknowledge with gratitude the study participants. We would also like to acknowledge and thank Claire O’Connell, Simone Lepage, Aoife O’Shaughnessy and Louise Foley for their support with the research project. Trial funder This research was funded by the Health Research Board in Ireland, through the Health Research Board – Trials Methodology Research Network as part of a Knowledge Exchange and Dissemination Scheme Award 2018 (grant reference KEDS-2018-012). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit.Peer reviewedPublisher PD