A5022431818- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Influenza Virus Research Studies
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Diabetes and associated disorders
- Cancer Genomics and Diagnostics
- HER2/EGFR in Cancer Research
- CAR-T cell therapy research
- vaccines and immunoinformatics approaches
- DNA Repair Mechanisms
- Reproductive System and Pregnancy
- Advanced Breast Cancer Therapies
- PARP inhibition in cancer therapy
- Monoclonal and Polyclonal Antibodies Research
- Reproductive Biology and Fertility
- Respiratory viral infections research
- CRISPR and Genetic Engineering
- Otitis Media and Relapsing Polychondritis
- Vasculitis and related conditions
- Chemokine receptors and signaling
- Breast Cancer Treatment Studies
- Immune cells in cancer
- Ovarian cancer diagnosis and treatment
- Immune Response and Inflammation
The University of Melbourne
2016-2025
Peter Doherty Institute
2016-2025
Peter MacCallum Cancer Centre
2020-2023
Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes known to elicit potent immunity a broad range of bacteria, mainly via the rapid production inflammatory cytokines. Whether MAIT contribute antiviral is less clear. Here we asked whether produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 pneumonia showed that individuals who recovered had higher numbers CD161(+)Vα7.2(+) peripheral blood...
Analysis of influenza-specific B cells during antigen exposure and tissue compartmentalization provides insights into human cell memory.
Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT also activated during viral infections, yet it remains unknown whether play a significant protective or even detrimental role infections vivo. Using murine experimental challenge with two strains of influenza A virus, we show that accumulate early infection, upregulation CD25, CD69 Granzyme...
The human lung harbors a large population of resident memory T cells (Trm cells). These are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, highly contagious pathogen that continues be major public health burden. Animal models show influenza-specific CD8+ Trm indispensable for crossprotection pulmonary infection with different virus strains. However, it is not known whether present within the have same critical role in modulating course...
CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated favorable prognosis in patients triple-negative breast cancer (TNBC). However, the relative contribution of TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy remains unknown. Here, we show that intratumoral murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic transcriptional studies established two sub-populations: one more enriched...
Abstract Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8 + T-cell profiles from patients hospitalized avian H7N9, seasonal IAV, and vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38 HLA-DR PD-1 T cells, whereas the prolonged persistence this set found in ultimately fatal cases. Single-cell cell receptor (TCR)-αβ analyses cells similar TCRαβ diversity but differential clonal expansion...
CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory change throughout the human lifetime and across tissue compartments, we investigated how cell receptor (TCR) composition diversity relate to anatomical sites immunological phases of life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both TCR-alpha (TCRα) TCR-beta (TCRβ) chains, new...
Abstract Newly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8 + T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding receptor (TCRαβ) cross-reactivity towards IAV variants is needed for vaccine design. Here, we investigate TCRαβ cross-strain recognition across two immunodominant...
Abstract How innate and adaptive immune responses work in concert to resolve influenza disease is yet be fully investigated one single study. Here, we utilize longitudinal samples from patients hospitalized with acute understand these responses. We report the dynamics of 18 important parameters, related clinical, genetic virological factors, across different severity levels. Influenza correlates increases IL-6/IL-8/MIP-1α/β cytokines lower antibody Robust activation circulating T follicular...
Abstract CD8 + T cells provide robust antiviral immunity, but how epitope-specific evolve across the human lifespan is unclear. Here we defined cell immunity directed at prominent influenza epitope HLA-A*02:01-M1 58–66 (A2/M1 58 ) four age groups phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence reset in older adults. Gene profiles adults closely resemble those of children,...
Abstract Influenza epidemics lead to severe illness, life-threatening complications, and deaths, especially in the elderly. As CD8+ T cells are associated with rapid recovery from influenza, we investigated effects of aging on antigen-specific across universal influenza epitopes humans. We show that is characterized by altered frequencies cell subsets, naive being partially replaced activated effector/memory populations. Although observed no striking differences TCR signaling capacity,...
Although γδ T cells comprise up to 10% of human peripheral blood cells, questions remain regarding their role in disease states and T-cell receptor (TCR) clonal expansions. We dissected anti-viral functions towards influenza viruses defined influenza-reactive TCRs the context γδ-TCRs across lifespan.We performed 51Cr-killing assay single-cell time-lapse live video microscopy define mechanisms underlying T-cell-mediated killing influenza-infected targets. assessed cytotoxic profiles patients...
Abstract Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT altered during different phases across the human life span is largely unknown. also abundant tissues, study focuses on cell analyses blood. Across span, we show that naive-like umbilical cord blood switch a central/effector memory-like profile sustained into older age. Whereas...
Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate combined PARP and WEE1 inhibition synergistic controlling tumour growth BRCA1/2 wild-type TNBC preclinical models. The inhibitor (PARPi) olaparib (WEE1i) adavosertib triggered increases anti-tumour immune responses, including STING pathway activation. Combinations a agonist resulted further improved durable regression significant...
Cross-reactive αβ T cell receptors (TCRs) recognizing multiple peptide variants can provide effective control of rapidly evolving viruses yet remain understudied. By screening 12 naturally occurring influenza-derived HLA-B*35:01–restricted nucleoprotein (NP) 418–426 epitopes (B*35:01-NP 418 ) that emerged since 1918 within influenza A viruses, including 2024 A/H5N1 we identified functional broadly cross-reactive cells universally NP variants. Binding studies demonstrated TCR cross-reactivity...
Abstract Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with disease are largely unknown. As the HLA-A*68:01 allele can be linked pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8 + T cells mount robust responses. We elucidate cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP 145...
Abstract Background Programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor proven clinical benefit the setting trastuzumab resistance. We investigated if tucatinib can alter tumor microenvironment this could be harnessed for therapeutic efficacy. Methods antitumor contribution of immune response using 2...
Abstract Special AT ‐rich binding protein‐1 ( SATB 1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role 1 pivotal for T‐cell development, with 1‐knockout being neonatally lethal, although the exact mechanism unknown. Moreover, dysregulated lymphoma proposed to suppress Pdcd1 gene, encoding immune checkpoint programmed cell death protein PD ‐1). Thus, expression subsets across different tissue compartments humans potential...
Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people. CD8+ T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human viruses. Several universally-conserved specificities that elicit prominent A viruses (IAVs) have been identified. These include HLA-A*02:01-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226,...