Ian H Frazer

University of Queensland | UQ · Diamantina Institute

Objectives Langerhans cells (LCs) are epithelial antigen‐presenting cells (APC) contributing to immune surveillance. LCs depend on interleukin 34 (IL34) production by epithelial cells. This study aimed to uncover mechanisms of alteration of IL34 and LC function in squamous cell carcinoma (SCC). Methods Cancer cohort data were used to identify asso...

The human gut microbiome is intrinsically involved in health and disease, representing a wealth of untapped therapeutic potential. Here, we demonstrate the utility and potential of a metagenome guided, large cohort-based approach for the rational selection of live biotherapeutics from the human gut. We applied this approach to Inflammatory Bowel Di...

Background: Persistent human papillomavirus (HPV) infection of basal keratinocytes (KC) can lead to malignant transformation, often associated with local immune suppression. We previously observed in a murine model of HPV-induced dysplastic epithelium an association between decreased T cell activation upon intradermal immunisation and impaired anti...

9514 Background: Neoadjuvant anti-Programmed Death therapy has shown a 64% complete or major pathological response rate in patients (pts) with resected stage II-IV(M0) cSCC. The De-Squamate study (NCT05025813) evaluated the feasibility of a risk adapted surgical de-escalation approach guided by clinical, radiological and pathological response in re...

Human cutaneous squamous cell carcinomas (SCCs) and actinic keratoses (AK) display microbial dysbiosis with an enrichment of staphylococcal species, which have been implicated in AK and SCC progression. SCCs are common in both felines and canines and are often diagnosed at late stages leading to high disease morbidity and mortality rates. Although...

Background Skin cancers, particularly keratinocyte cancers, are the most commonly diagnosed tumors. Although surgery is often effective in early-stage disease, skin tumors are not always easily accessible, can reoccur and have the ability to metastasize. More recently, immunotherapies, including intravenously administered checkpoint inhibitors, hav...

Immune checkpoint inhibitor (ICI) therapy has had limited success (<30%) in treating metastatic recurrent Head and Neck Oropharyngeal Squamous Cell Carcinomas (OPSCCs). We postulate that spatial determinants in the tumor play a critical role in cancer therapy outcomes. Here, we describe the case of a male patient diagnosed with p16+ OPSCC and exten...

Background Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and a...

Background: Despite the rising incidence, particularly of the human papillomavirus (HPV)-associated fraction of oropharyngeal cancer (OPC), there are no early detection methods for OPC. Considering the close association between saliva and head and neck cancers, this study was designed to investigate salivary micro RNA (miRNAs) associated with OPC,...

Immune checkpoint inhibitor (ICI) modality has had a limited success (<20%) in treating metastatic recurrent Head & Neck Oropharyngeal Squamous cell carcinomas (OPSCCs). To improve response rates to ICIs, tailored approaches capable to capture the tumor complexity and dynamics of each patient's disease are needed. Here, we performed advanced analys...

Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in h...

Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy...

Macrophages are one of the essential components of the tumour microenvironment (TME) of many cancers and show complex heterogeneity and functions. More recent research has been focusing on the characterisation of tumour-associated macrophages (TAMs). Previously, our study demonstrated that caerin 1.1/1.9 peptides significantly improve the therapeut...

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 Databa...

A single dose of human papillomavirus (HPV) vaccine against HPV infection (prerequisite for cervical cancer) appears to be as efficacious as two or three doses, despite inducing lower antibody titers. Neutralizing antibodies are thought to be the primary mediator of protection, but the threshold for protection is unknown. Antibody functions beyond...

Actinic keratosis (AK) is a premalignant lesion, common on severely photodamaged skin, that can progress over time to cutaneous squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC, but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus can...

Background Although the majority of human papillomavirus (HPV) infections are cleared by the immune system, a small percentage of them progress to develop HPV‐driven cancers. Cervical cancer studies highlight that HPV persistence and cancer risk are associated with genetic factors, especially at the human leukocyte antigen (HLA) genes. This study w...

Actinic keratoses (AK) arise in severely photo-damaged skin and can progress to squamous cell carcinomas (SCC). AK and SCC are common in Caucasian populations, and immunosuppressed individuals have a markedly higher risk of developing SCC. An overabundance of Staphylococcus aureus has been reported in AK and SCC lesions of immunocompetent individua...

Squamous cell carcinoma (SCC) is a common type of skin cancer that typically arises from premalignant precursor lesions named actinic keratoses (AK). Chronic inflammation is a well-known promoter of skin cancer progression. AK and SCC have been associated with an overabundance of the bacterium Staphylococcus aureus ( S. aureus ). Certain secreted p...

Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by HPV16...

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 specie...

Objectives Developing a vaccine formula that alters the tumor-infiltrating lymphocytes to be more immune active against a tumor is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen-specific immunotherapy, and IL-10 and PD-1 blockade, intratumoral administration of caerin 1.1/1.9...

The last decade has seen a continued escalation in rates of human papillomavirus related oropharyngeal malignancy (HPV-OPC). This has occurred despite established national vaccination programs. In contrast, HPV associated cervical cancer incidence rates have declined, due in part to effective cervical cancer screening programs, many of which have m...

High-risk human papillomavirus (HR-HPV) infection is one of the major risk factors for head and neck cancers (HNC). Despite the rising incidence, biomarkers for detection, prognostication and disease monitoring of HPV-driven HNC (HPV-HNC) are lacking. To evaluate the capacity of salivary HR-HPV DNA as a biomarker for HPV-HNC, salivary HR-HPV status...

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 trial...

Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establ...

Significance The immune system relies on coordinated interactions between motile cells guided by molecules known as chemokines. However, processes that control chemokine distribution in complex in vivo microenvironments are poorly understood. Dendritic cells in barrier tissues require the chemokine CCL21 to enter lymphatic vessels during tissue egr...

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...

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. M...

Background: We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: Eligible subject...

Regulatory T cells (Tregs) are recruited to nonlymphoid tissues in chronic disease, including cancer, and the tissue environment is held to shape the Treg phenotype diversity. Using single-cell RNA sequencing, we examined the transcriptomic and TCR profile of Tregs recruited to hyperproliferative HPV16 E7-expressing transgenic and control nontransg...

Prophylactic human papillomavirus (HPV) vaccines are commercially available for prevention of infection with cancerogenic HPV genotypes but are not able to combat pre-existing HPV-associated disease. In this study, we designed a nanomaterial-based therapeutic HPV vaccine, comprising manganese (Mn4+)-doped silica nanoparticles (Mn4+-SNPs) and the vi...

Human papillomavirus (HPV) vaccines are safe and effective in preventing HPV infection and cervical precancers. Neutralizing antibodies are thought to be the primary mechanism of protection for HPV vaccines, although the exact level required for protection has not been identified. Three common serological assays used in clinical trials to measure H...

The ability to study cancer-immune cell communication across the whole tumor section without tissue dissociation is important to understand molecular mechanisms of cancer immunotherapy and drug targets. Current experimental methods such as immunohistochemistry allow researchers to investigate a small number of cells or a limited number of ligand-re...

Development of a vaccine formula that alters the tumour-infiltrating lymphocytes to be more immune active against a tumour is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen specific immunotherapy, and IL-10 and PD-1 blockade, intra-tumoral administration of caerin 1.1 and 1.9...

Given that oropharyngeal squamous cell carcinoma (OPSCC) have now surpassed cervical cancer as the most common human papillomavirus (HPV)‐driven cancer, there is an interest in developing non‐invasive predictive biomarkers to early detect HPV‐driven OPSCC. A total of 665 cancer‐free individuals were recruited from Queensland, Australia. Oral HPV16...

Human papillomavirus (HPV) infection is associated with a range of malignancies that affect anogenital and oropharyngeal sites. α-HPVs dominantly infect basal epithelial cells of mucosal tissues, where they dysregulate cell division and local immunity. The cervix is one of the mucosal sites most susceptible to HPV infections. It consists of anatomi...

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor...

Cytokines are commonly measured by immunoassays; however, these have limited multiplexing capacity, are costly, and can exhibit cross-reactivity. Multiple reaction monitoring (MRM) mass spectrometry is a robust method to quantify analytes with high specificity and multiplexing ability, hence we aimed to investigate its suitability as an alternative...

Objective Tongue squamous cell carcinoma is one of the most common oral tumors. Human papillomavirus (HPV) infection has been proposed as a risk factor for head and neck squamous cell carcinoma, particularly oropharyngeal squamous carcinoma. Methods In this study, we retrospectively analyzed HPV infection in 121 Chinese patients with tongue squamo...

Background Genital herpes simplex infection affects more than 500 million people worldwide. We have previously shown that COR-1, a therapeutic HSV-2 polynucleotide vaccine candidate, is safe and well tolerated in healthy subjects. Objective Here, we present a single center double-blind placebo-controlled, randomized phase I/IIa trial of COR-1 in H...

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define wheth...

Background Staphylococcus aureus is well known to be associated with atopic dermatitis. Recent studies also report S. aureus presence in lesional skin of squamous cell carcinoma (SCC) and its precursor lesion, actinic keratosis (AK). Therefore, it is of potential clinical interest to monitor skin S. aureus colonization on AK lesions. Fourier transf...

Adjuvants play an essential function in vaccine formulations by boosting immune responses to the delivered antigen. Mark A. F. Kendall and colleagues investigate the efficacy of vaccine delivered intradermally via NanopatchTM—a 16 mm2 ultra-high-density array of 100 micron needles. Systems analysis comparisons demonstrate that depending on the forc...

Human papillomavirus (HPV) related tumours account for a significant proportion of head and neck squamous cell carcinomas (HNSCCs) in developed countries. They respond better to chemo- and radio-therapy, and have a better stage specific prognosis. To establish their prevalence in China, we assessed a series of histology confirmed HNSCCs collected i...

Human Papillomavirus infection is highly prevalent worldwide. While most types of HPV cause benign warts, some high-risk types are known to cause cervical cancer, as well as cancer of the oral cavity and head and neck. Persistent cutaneous HPV infection can be particularly problematic in patients with chronic immunosuppression, for example followin...

Human papillomaviruses infect keratinocytes and can lead to hyperproliferative dysplasia and malignant transformation if not cleared by the immune system. Human papillomavirus has evolved an array of mechanisms to evade and manipulate the immune system to improve replication efficiency and promote persistent infection. We here demonstrate that hype...

The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is rising in high-income countries, including Australia. Increasing evidence suggests that accurate HPV testing is pivotal for clinical decision making and treatment planning in these patients. Recently, the eighth edition of the American Joint Committee on Cancer/Union...

Objective Australia's HPV vaccination and HPV-based cervical screening programs are changing the landscape in cervical cancer prevention. We aim to identify areas which can make the biggest further impact on cervical cancer burden. This protocol describes the first stage of a program of work called Pathways-Cervix that aims to generate evidence fro...

“High-risk” human papillomaviruses (HPV) infect keratinocytes of squamous epithelia. The HPV16E7 protein induces epithelial hyperplasia by binding Rb family proteins and disrupting cell cycle termination. Murine skin expressing HPV16E7 as a transgene from a keratin 14 promoter (K14.E7) demonstrates epithelial hyperplasia, dysfunctional antigen pres...

Background Accumulating evidence has suggested the utility of salivary oral rinse as a diagnostic fluid to detect oral human papillomavirus (HPV) DNA, but there are many methods for collecting saliva. Methods Salivary oral rinse and unstimulated whole mouth saliva samples were collected from 45 oropharyngeal cancer (OPC) patients. Results We show...

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. I...

Waterfall plot of significant mutations identified by MuTect, MuTect2 or VarScan2. Mutations are ranked accordingly to significance assigned by MutSigCV analysis. Clinical traits are matched to the samples and displayed as a heat map. Tumor purity and ploidy values predicted from BubbleTree are included. (EPS)

Consensus WGCNA network analysis between TCGA HNSC-OCSCC and BNE PAH OCSCC RNA-seq data. (A) Module preservation z-score of modules detected in consensus gene network. Higher z-score indicates higher module preservation/similarity (>10 z-score). (B) Correlation of modules detected in consensus gene network with clinical trait measurements is shown...

BubbleTree Tumor purity estimates for samples 1–10. The BubbleTree graph is presented with the R score (copy number ratio) on the x-axis and the HDS (heterozygous-deviation score; |Beta allele frequency– 0.5|) on the y-axis. The proximity of the bubbles (somatic copy number alterations), or leaves, to the tree branches indicates the integer allele-...

BubbleTree Tumor purity estimates for samples 11–20. The BubbleTree graph is presented with the R score (copy number ratio) on the x-axis and the HDS (heterozygous-deviation score; |Beta allele frequency– 0.5|) on the y-axis. The proximity of the bubbles (somatic copy number alterations), or leaves, to the tree branches indicates the integer allele...

BubbleTree Tumor purity estimates for samples 21–25. The BubbleTree graph is presented with the R score (copy number ratio) on the x-axis and the HDS (heterozygous-deviation score; |Beta allele frequency– 0.5|) on the y-axis. The proximity of the bubbles (somatic copy number alterations), or leaves, to the tree branches indicates the integer allele...

Differential gene testing between smoking groups. Differential gene expression testing between the smoking groups (Current versus Ex; Current versus Never; Ex vs Never) using LIMMA-voom. Genes were considered statistically significanct if they met the fold-change threshold of > 1.25 or < -1.25 and Benjamini and Hochberg (BH) adjusted p-value of < 0...

Normalized read counts of HPV16 E7 gene. Reads from RNA-seq data (33 samples) were aligned to the human reference genome concatenated with HPV16 (NC_001526.4) genome and represented as normalized read counts per million for the HPV16 E7 oncogene. (EPS)

Cutaneous squamous cell carcinoma (SCC) is the second-most-common cancer in Australia. The majority of SCCs progress from premalignant actinic keratosis (AK) lesions that form on chronically sun-exposed skin. The role of skin microbiota in this progression is not well understood; therefore, we performed a longitudinal microbiome analysis of AKs and...

Background Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflam...

EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in 3D culture. These studies have been completed via genetic sequencing, cell line or 3D in vitro and in vivo murine models. Here we describe an imaging method t...