A5068354382- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- CRISPR and Genetic Engineering
- Viral Infectious Diseases and Gene Expression in Insects
- Autoimmune and Inflammatory Disorders Research
- Advancements in Semiconductor Devices and Circuit Design
- Cancer, Stress, Anesthesia, and Immune Response
- Adolescent and Pediatric Healthcare
- Acute Lymphoblastic Leukemia research
- Nanowire Synthesis and Applications
- Chemokine receptors and signaling
- T-cell and B-cell Immunology
- Cancer Mechanisms and Therapy
- Childhood Cancer Survivors' Quality of Life
- Signaling Pathways in Disease
- Adenosine and Purinergic Signaling
- Extracellular vesicles in disease
- Polyamine Metabolism and Applications
- MicroRNA in disease regulation
- Kruppel-like factors research
- interferon and immune responses
- Single-cell and spatial transcriptomics
Peter MacCallum Cancer Centre
2015-2024
The University of Melbourne
2014-2023
Abstract Purpose: Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor infiltrate, but mechanisms underlying recruitment T cells following therapy are poorly characterized. A greater understanding these processes may see development therapeutic interventions that enhance T-cell and, consequently, improved patient outcomes. We therefore investigated chemokines essential for cell and subsequent efficacy immunotherapies. Experimental...
Abstract Adenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation adenosine A 2A receptor (A R). Using both murine and human chimeric antigen (CAR) cells, here we show targeting R with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival mice. Effects evoked by mediated gene deletion are superior shRNA knockdown or...
Abstract Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B lymphoma and multiple myeloma 1–4 , but efficacy CAR in solid tumours been limited 5 . This is owing to a number factors, including immunosuppressive tumour microenvironment that gives rise poorly persisting metabolically dysfunctional cells. Analysis anti-CD19 cells used clinically shown positive outcomes are associated with more...
Abstract The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control metastatic B16F10 growth relative to mice. Analyses this interplay human samples reveal high expression a cell gene signature negatively impacts the prognostic significance cells. Paradoxically, pre-pulsing tumors with antigens, or activating vivo, enhances anti-tumor and E0771 mouse models,...
Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR cells solid tumors is limited by tumor-induced immunosuppression, development combination approaches, such as adjuvant programmed death 1 (PD-1) blockade. Current FDA-approved methods for generating utilize either anti-CD3 interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a product...
Abstract CRISPR/Cas9 technologies have revolutionized our understanding of gene function in complex biological settings, including T cell immunology. Current CRISPR-mediated editing strategies cells require vitro stimulation or culture that can both preclude the study unmanipulated naive and alter subsequent differentiation. In this study, we demonstrate highly efficient within uncultured primary murine CD8+ by electroporation recombinant Cas9/sgRNA ribonucleoprotein immediately prior to...
Abstract Immunotherapy is widely accepted as a powerful new treatment modality for the of cancer. The most successful form immunotherapy to date has been blockade immune checkpoints PD-1 and CTLA-4. Combining inhibitors both CTLA-4 increases proportion patients who respond immunotherapy. However, still do not checkpoint inhibitors, prognostic biomarkers are currently lacking. Therefore, better understanding mechanism by which these enhance antitumor responses required more accurately predict...
The production and delivery of functional perforin (PRF; PRF1 gene) by cytotoxic lymphocytes maintains immune homeostasis tumour surveillance. In humans, inheritance the common polymorphism, p.A91V, (c.272C>T) found in 8–9% Caucasian population, with another mutated allele resulting reduced PRF function or trafficking, has been shown to result hyperinflammatory diseases and/or haematological cancers. this study, we sought investigate p.A91V on a wild‐type (WT) background. We first...
Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor therapeutic efficacy. A determinant TME composition is location, and clinical data have revealed associations between certain metastatic sites reduced responses. Preclinical models study tissue-specific TMEs eliminated genetic heterogeneity, but investigated with limited relevance.We tumors at clinically relevant metastasis (liver lungs) their...
Perforin, a pore-forming toxin released from secretory granules of NK cells and CTLs, is essential for their cytotoxic activity against infected or cancerous target cells. Bi-allelic loss-of-function mutations in the perforin gene are invariably associated with fatal immunoregulatory disorder, familial haemophagocytic lymphohistiocytosis type 2 (FHL2), infants. More recently, it has also been recognized that partial loss function can cause disease later life, including delayed onset FHL2...
CXCL9 expression is a strong predictor of response to immune checkpoint blockade therapy. Accordingly, we sought develop therapeutic strategies enhance the and augment antitumor immunity. To perform whole-genome CRISPR-Cas9 screening for regulators expression, CXCL9-GFP reporter line generated using CRISPR knockin strategy. This approach finds that IRF1 limits in both tumor cells primary myeloid through induction SOCS1, which subsequently STAT1 signaling. Thus, identify subset...
Cytotoxic lymphocytes destroy pathogen-infected and transformed cells through the cytotoxic granule exocytosis death pathway, which is dependent on delivery of proapoptotic granzymes into target cell cytosol by pore-forming protein, perforin. Despite importance mouse models in understanding role immune-mediated disease their cancer immune surveillance, no reliable intracellular detection method exists for Consequently, rapid, flow-based assessment potential has been problematic, complex...
Abstract MR1-restricted mucosal-associated invariant T (MAIT) cells recognize microbial metabolites and play an important role in immunity to infection, however, the they tumor is unclear. Here we show that MAIT cell-deficient mice are more resistant subcutaneous lung metastasis B16F10 growth compared control mice, effect was associated with enhanced NK cell numbers cell-dependent. Analysis of this interplay cancer patients also revealed a high expression novel gene signature negatively...
Interferon gamma (IFNγ) is a pro-inflammatory cytokine that directly activates the JAK/STAT pathway. However, temporal dynamics of chromatin remodeling and transcriptional activation initiated by IFNγ have not been systematically profiled in an unbiased manner. Herein, we integrated transcriptomic epigenomic profiling to characterize acute epigenetic changes induced stimulation murine breast cancer model.We identified de novo cis-regulatory elements bound Irf1 were characterized increased...
Abstract The efficacy of Chimeric Antigen Receptor (CAR) T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment (TME) including adenosine, which suppresses CAR through activation A2A receptor (A2AR). To overcome this, were engineered to express A1R, a that signals inversely A2AR. Using murine and human cells, constitutive A1R overexpression was demonstrated significantly enhance cell effector function albeit at expense persistence. Through novel...
Abstract There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for the A 2A R receptor. Understanding of mechanism by which regulated has hindered difficulty identifying cell types that express due to a lack robust antibodies these receptors. To overcome this limitation, here an eGFP reporter mouse developed, enabling expression during ongoing anti-tumor immune responses be assessed. This reveals...