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Article ; Online: Collaboration in the War against Viruses

Ian H. Frazer

The Innovation, Vol 1, Iss 1, Pp 100011- (2020)

A Multidisciplinary International Effort

2020

Keywords	Science (General) ; Q1-390
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immune-Inhibitory Gene Expression is Positively Correlated with Overall Immune Activity and Predicts Increased Survival Probability of Cervical and Head and Neck Cancer Patients

Megha Budhwani / Gavin Turrell / Meihua Yu / Ian H. Frazer / Ahmed M. Mehdi / Janin Chandra

Frontiers in Molecular Biosciences, Vol

2021 Volume 8

Abstract: Background: Limited immunotherapy options are approved for the treatment of cervical cancer and only 10–25% of patients respond effectively to checkpoint inhibition monotherapy. To aid the development of novel therapeutic immune targets, we aimed to ... ...

Abstract	Background: Limited immunotherapy options are approved for the treatment of cervical cancer and only 10–25% of patients respond effectively to checkpoint inhibition monotherapy. To aid the development of novel therapeutic immune targets, we aimed to explore survival-associated immune biomarkers and co-expressed immune networks in cervical cancer.Methods: Using The Cancer Genome Atlas (TCGA) Cervical Squamous Cell Carcinoma (CESC) data (n = 304), we performed weighted gene co-expression network analysis (WGCNA), and determined which co-expressed immune-related genes and networks are associated with survival probability in CESC patients under conventional therapy. A “Pan-Immune Score” and “Immune Suppression Score” was generated based on expression of survival-associated co-expressed immune networks and immune suppressive genes, which were subsequently tested for association with survival probablity using the TCGA Head Neck Squamous Cell Carcinoma (HNSCC) data (n = 528), representing a second SCC cancer type.Results: In CESC, WGCNA identified a co-expression module enriched in immune response related genes, including 462 genes where high expression was associated with increased survival probability, and enriched for genes associated with T cell receptor, cytokine and chemokine signaling. However, a high level of expression of 43 of the genes in this module was associated with decreased survival probability but were not enriched in particular pathways. Separately, we identified 20 genes associated with immune suppression including inhibitory immune checkpoint and regulatory T cell-related genes, where high expression was associated with increased survival probability. Expression of these 20 immune suppressive genes (represented as “Immune Suppression Score”) was highly correlated with expression of overall survival-associated immune genes (represented as “Pan-Immune Score”). However, high expression of seven immune suppression genes, including TWEAK-R, CD73, IL1 family and TGFb family genes, was significantly ...
Keywords	cervical cancer ; head and neck cancer ; inflamed tumours ; immune inhibition ; immune checkpoints ; prognosis ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Environmental pathways affecting gene expression (E.PAGE) as an R package to predict gene–environment associations

Sachin Muralidharan / Sarah Ali / Lilin Yang / Joshua Badshah / Syeda Farah Zahir / Rubbiya A. Ali / Janin Chandra / Ian H. Frazer / Ranjeny Thomas / Ahmed M. Mehdi

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 19

Abstract: Abstract The purpose of this study is to manually and semi-automatically curate a database and develop an R package that will act as a comprehensive resource to understand how biological processes are dysregulated due to interactions with environmental ... ...

Abstract	Abstract The purpose of this study is to manually and semi-automatically curate a database and develop an R package that will act as a comprehensive resource to understand how biological processes are dysregulated due to interactions with environmental factors. The initial database search run on the Gene Expression Omnibus and the Molecular Signature Database retrieved a total of 90,018 articles. After title and abstract screening against pre-set criteria, a total of 237 datasets were selected and 522 gene modules were manually annotated. We then curated a database containing four environmental factors, cigarette smoking, diet, infections and toxic chemicals, along with a total of 25,789 genes that had an association with one or more of gene modules. The database and statistical analysis package was then tested with the differentially expressed genes obtained from the published literature related to type 1 diabetes, rheumatoid arthritis, small cell lung cancer, COVID-19, cobalt exposure and smoking. On testing, we uncovered statistically enriched biological processes, which revealed pathways associated with environmental factors and the genes. The curated database and enrichment tool are available as R packages at https://github.com/AhmedMehdiLab/E.PATH and https://github.com/AhmedMehdiLab/E.PAGE respectively.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epithelium Expressing the E7 Oncoprotein of HPV16 Attracts Immune-Modulatory Dendritic Cells to the Skin and Suppresses Their Antigen-Processing Capacity.

Janin Chandra / Yan Miao / Natasha Romoff / Ian H Frazer

PLoS ONE, Vol 11, Iss 3, p e

2016 Volume 0152886

Abstract: Antigen presenting cells (APCs) in skin can promote either antigen-specific effector functions or antigen tolerance, and thus determine clearance or persistence of cutaneous viral infections. Human papillomavirus (HPV) infections can persist in squamous ... ...

Abstract	Antigen presenting cells (APCs) in skin can promote either antigen-specific effector functions or antigen tolerance, and thus determine clearance or persistence of cutaneous viral infections. Human papillomavirus (HPV) infections can persist in squamous epithelium in immunocompetent individuals, and some persisting HPV infections, particularly with HPV16, promote malignant epithelial transformation. Here, we investigate whether local expression of the HPV16 protein most associated with malignant transformation, HPV16-E7, affects the phenotype and function of APC subsets in the skin. We demonstrate an expanded population of Langerhans cells in HPV16-E7 transgenic skin with distinct cell surface markers which express immune-modulatory enzymes and cytokines not expressed by cells from non transgenic skin. Furthermore, HPV16-E7 transgene expression in keratinocytes attracts new APC subsets to the epidermis. In vivo migration and transport of antigen to the draining lymph node by these APCs is markedly enhanced in HPV16-E7 expressing skin, whereas antigen-processing, as measured by proteolytic cleavage of DQ-OVA and activation of T cells in vivo by APCs, is significantly impaired. These data suggest that local expression of HPV16-E7 in keratinocytes can contribute to persisting infection with this oncogenic virus, by altering the phenotype and function of local APCs.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Acquisition of murine splenic myeloid cells for protein and gene expression profiling by advanced flow cytometry and CITE-seq

Inga Rødahl / James Gotley / Stacey B. Andersen / Meihua Yu / Ahmed M. Mehdi / Angelika N. Christ / Emma E. Hamilton-Williams / Ian H. Frazer / Samuel W. Lukowski / Janin Chandra

STAR Protocols, Vol 2, Iss 4, Pp 100842- (2021)

2021

Abstract: Summary: Here, we outline detailed protocols to isolate and profile murine splenic dendritic cells (DCs) through advanced flow cytometry of the myeloid compartment and single-cell transcriptomic profiling with integrated cell surface protein expression ... ...

Abstract	Summary: Here, we outline detailed protocols to isolate and profile murine splenic dendritic cells (DCs) through advanced flow cytometry of the myeloid compartment and single-cell transcriptomic profiling with integrated cell surface protein expression through CITE-seq. This protocol provides a general transferrable road map for different tissues and species.For complete details on the use and execution of this protocol, please refer to Lukowski et al. (2021).
Keywords	Sequence analysis ; Cell isolation ; Single Cell ; Flow Cytometry/Mass Cytometry ; Health Sciences ; Sequencing ; Science (General) ; Q1-390
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Absence of Batf3 reveals a new dimension of cell state heterogeneity within conventional dendritic cells

Samuel W. Lukowski / Inga Rødahl / Samuel Kelly / Meihua Yu / James Gotley / Chenhao Zhou / Susan Millard / Stacey B. Andersen / Angelika N. Christ / Gabrielle Belz / Ian H. Frazer / Janin Chandra

iScience, Vol 24, Iss 5, Pp 102402- (2021)

2021

Abstract: Summary: Conventional dendritic cells (cDCs) are traditionally subdivided into cDC1 and cDC2 lineages. Batf3 is a cDC1-required transcription factor, and we observed that Batf3−/− mice harbor a population of cDC1-like cells co-expressing cDC2-associated ... ...

Abstract	Summary: Conventional dendritic cells (cDCs) are traditionally subdivided into cDC1 and cDC2 lineages. Batf3 is a cDC1-required transcription factor, and we observed that Batf3−/− mice harbor a population of cDC1-like cells co-expressing cDC2-associated surface molecules. Using single-cell RNA sequencing with integrated cell surface protein expression (CITE-seq), we found that Batf3−/− mitotic immature cDC1-like cells showed reduced expression of cDC1 features and increased levels of cDC2 features. In wild type, we also observed a proportion of mature cDC1 cells expressing surface features characteristic to cDC2 and found that overall cDC cell state heterogeneity was mainly driven by developmental stage, proliferation, and maturity. We detected population diversity within Sirpa+ cDC2 cells, including a Cd33+ cell state expressing high levels of Sox4 and lineage-mixed features characteristic to cDC1, cDC2, pDCs, and monocytes. In conclusion, these data suggest that multiple cDC cell states can co-express lineage-overlapping features, revealing a level of previously unappreciated cDC plasticity.
Keywords	Immunology ; Cell Biology ; Transcriptomics ; Science ; Q
Subject code	612
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolution of Cancer Vaccines—Challenges, Achievements, and Future Directions

Ban Qi Tay / Quentin Wright / Rahul Ladwa / Christopher Perry / Graham Leggatt / Fiona Simpson / James W. Wells / Benedict J. Panizza / Ian H. Frazer / Jazmina L. G. Cruz

Vaccines, Vol 9, Iss 535, p

2021 Volume 535

Abstract: The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these ... ...

Abstract	The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.
Keywords	vaccine ; cancer ; antigens ; ICIs ; immunotherapies ; T-cells ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The kinematics of cytotoxic lymphocytes influence their ability to kill target cells.

Purnima Bhat / Graham Leggatt / Klaus I Matthaei / Ian H Frazer

PLoS ONE, Vol 9, Iss 5, p e

2014 Volume 95248

Abstract: Cytotoxic lymphocytes (CTL) have been reported to show a range of motility patterns from rapid long-range tracking to complete arrest, but how and whether these kinematics affect their ability to kill target cells is not known. Many in vitro killing ... ...

Abstract	Cytotoxic lymphocytes (CTL) have been reported to show a range of motility patterns from rapid long-range tracking to complete arrest, but how and whether these kinematics affect their ability to kill target cells is not known. Many in vitro killing assays utilize cell lines and tumour-derived cells as targets, which may be of limited relevance to the kinetics of CTL-mediated killing of somatic cells. Here, live-cell microscopy is used to examine the interactions of CTL and primary murine skin cells presenting antigens. We developed a qualitative and quantitative killing assay using extended-duration fluorescence time-lapse microscopy coupled with large-volume objective software-based data analysis to obtain population data of cell-to-cell interactions, motility and apoptosis. In vivo and ex vivo activated antigen-specific cytotoxic lymphocytes were added to primary keratinocyte targets in culture with fluorometric detection of caspase-3 activation in targets as an objective determinant of apoptosis. We found that activated CTL achieved contact-dependent apoptosis of non-tumour targets after a period of prolonged attachment - on average 21 hours - which was determined by target cell type, amount of antigen, and activation status of CTL. Activation of CTL even without engagement of the T cell receptor was sufficient to mobilise cells significantly above baseline, while the addition of cognate antigen further enhanced their motility. Highly activated CTL showed markedly increased vector displacement, and velocity, and lead to increased antigen-specific target cell death. These data show that the inherent kinematics of CTL correlate directly with their ability to kill non-tumour cells presenting cognate antigen.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Role of Ultraviolet Radiation in Papillomavirus-Induced Disease.

Aayushi Uberoi / Satoshi Yoshida / Ian H Frazer / Henry C Pitot / Paul F Lambert

PLoS Pathogens, Vol 12, Iss 5, p e

2016 Volume 1005664

Abstract: Human papillomaviruses are causally associated with 5% of human cancers. The recent discovery of a papillomavirus (MmuPV1) that infects laboratory mice provides unique opportunities to study the life cycle and pathogenesis of papillomaviruses in the ... ...

Abstract	Human papillomaviruses are causally associated with 5% of human cancers. The recent discovery of a papillomavirus (MmuPV1) that infects laboratory mice provides unique opportunities to study the life cycle and pathogenesis of papillomaviruses in the context of a genetically manipulatable host organism. To date, MmuPV1-induced disease has been found largely to be restricted to severely immunodeficient strains of mice. In this study, we report that ultraviolet radiation (UVR), specifically UVB spectra, causes wild-type strains of mice to become highly susceptible to MmuPV1-induced disease. MmuPV1-infected mice treated with UVB develop warts that progress to squamous cell carcinoma. Our studies further indicate that UVB induces systemic immunosuppression in mice that correlates with susceptibility to MmuPV1-associated disease. These findings provide new insight into how MmuPV1 can be used to study the life cycle of papillomaviruses and their role in carcinogenesis, the role of host immunity in controlling papillomavirus-associated pathogenesis, and a basis for understanding in part the role of UVR in promoting HPV infection in humans.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2016-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Examining the contribution of smoking and HPV towards the etiology of oral cavity squamous cell carcinoma using high-throughput sequencing

Andrew P Zammit / Rohit Sinha / Caroline L Cooper / Christopher F L Perry / Ian H Frazer / Zewen K Tuong

PLoS ONE, Vol 13, Iss 10, p e

A prospective observational study.

2018 Volume 0205406

Abstract: Oral cavity Squamous Cell Carcinoma (OCSCC) is a common form of head and neck cancer throughout the developed and developing world. However, the etiology of OCSCC is still unclear. Here, we explored the extent to which tobacco use, Human Papillomavirus ( ... ...

Abstract	Oral cavity Squamous Cell Carcinoma (OCSCC) is a common form of head and neck cancer throughout the developed and developing world. However, the etiology of OCSCC is still unclear. Here, we explored the extent to which tobacco use, Human Papillomavirus (HPV) infection and genetic and transcriptomic changes contributed to the oncogenesis of OCSCC. In a prospective observational study, we analysed fresh tissue biopsies from 45 OCSCC collected from 51 subjects presenting with OCSCC to the Brisbane Head and Neck Clinics between 2013 and 2015. Exploration of the genetic and transcriptomic landscape of the biopsies were performed using RNA sequencing (RNA-seq) and whole exome sequencing. HPV associated tumours were determined using p16 staining of histological sections and RNA sequencing. Patient demographics including tumor location within the oral cavity, and history of tobacco and alcohol use were correlated with genomic and transcriptomics analyses. About 4.5% of OCSCC were HPV associated. The most frequent mutations in the OCSCC samples were in the TP53 and CDKN2A genes, but no association of specific mutations with HPV or tobacco use was observed. Using weighted gene co-expression network analysis to explore the RNA-seq data, tumors from participants with a history of tobacco use showed a significant trend towards increased mammalian target of Rapamycin (mTOR) signaling and decreased mitochondrial respiration. In conclusion, HPV was shown to be an uncommon association with OCSCC and changes in TP53 transcriptional regulation, mTOR signaling and mitochondrial function were associated with a history of tobacco use. Larger data sets will be required to enable detection of differences which may help with development of personalized therapeutics in the future.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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