Dr Graham Leggatt
|Dr Graham Leggatt|
Dr Graham Leggatt and his colleagues have discovered that something curious happens between the immune system and a tumour during the early stages of cancer development: increased cell production - called hyperplasia - attracts a lot of immune cells.
“We didn’t appreciate how early this process starts,” says Leggatt. “The cancer is dragging in cells that could kill the cancer but it also attracts cells that can suppress the immune system.” The tumour ultimately attracts more suppressor cells and establishes a protective microenvironment that fosters further growth. Leggatt believes a clearer understanding of that immediate immune environment could give rise to novel anti-cancer therapies.
Leggatt’s path toward immunology began early. “I was always interested in how things worked. In Grade 10, my science teacher really made me think about doing a science degree.”
Leggatt went on to complete a Bachelor of Science and an Honours degree in microbiology. As he pursued a PhD at the Queensland Institute for Medical Research (QIMR), he began working on the diagnosis of Hydatitid disease - a parasitic disease found mostly in animals, but transferable to humans.
This venture into parasite immunology was Leggatt’s first insight into translational research and it crafted the way for his current career in immunology. Leggatt soon embarked on post-doctoral research at the National Institutes of Health (NIH) in the US in the laboratory of Professor Jay Berzofsky, a well known immunologist who was working on HIV.
“We discovered that the quality of the T-cell response to a viral infection is very important," Leggatt says. A T-cell population can present billions of different possible receptors in response to an infection, he explains, but it became apparent that it isn’t the quantity of T-cells that matters, but how specific the T-cell receptors are to the invading pathogen.
In 1997, Leggatt met Professor Ian Frazer – co-inventor of the cervical cancer vaccine – while at an immunology conference in New York. The encounter led to an opportunity to work with Frazer at the University of Queensland’s Centre for Immunology and Cancer Research (CICR), so Leggatt returned to Australia to investigate the quality of T-cell responses in Human Papiloma Virus (HPV), the primary cause of cervical cancer.
His research focus soon shifted to immunotherapy. While the cervical cancer vaccine prevents HPV infection and therefore substantially reduces cervical cancer risk, Frazer, Leggatt and their colleagues began searching for ways to use the immune system to treat women already diagnosed with cervical cancer. Leggatt notes that he is grateful he had the opportunity, during his first years in the lab, to collaborate with the late virologist Dr Jian Zhou– co-inventor of the cervical cancer vaccine with Professor Frazer. “I benefited highly from that experience,” he says.
Leggatt is now a Senior Research Fellow at the University of Queensland Diamantina Institute (UQDI), where he is researching the immune environment in the skin and how its suppression allows early cancerous lesions to grow. He believes that advances in this area could not only guide the development of cervical cancer immunotherapies, but could also help explain how immunity is controlled in other epithelial cancers, including Squamous Cell Carcinoma.
Leggatt believes UQDI is an ideal place to carry out such research. “I am able to work with people like Ian who have vast knowledge and experience in epithelial cancer. There are also fantastic facilities available to us at the UQDI to do all the work – we can do just about anything we want to do.”
Dr Leggatt also enjoys lecturing part-time at The University of Queensland. “There’s a thrill in teaching the next generation of researchers in immunology.”
Telephone: +61 7 3443 6961
Trina Stewart – Peter MacCallum Cancer Institute, Melbourne, Australia
Sharmal Narayan - University of Lausanne, Lausanne, Switzerland
10 Recent Publications
Abd Warif, Nor Malia, Stoitzner, Patrizia, Leggatt, Graham R., Mattarollo, Stephen R., Frazer, Ian H. and Hibma, Merilyn H. (2015) Langerhans Cell Homeostasis and Activation Is Altered in Hyperplastic Human Papillomavirus Type 16 E7 Expressing Epidermis. PLoS One, 10 5: e0127155-e0127155. doi:10.1371/journal.pone.0127155
McKee, Sara J., Bergot, Anne-Sophie and Leggatt, Graham R. (2015) Recent progress in vaccination against human papillomavirus-mediated cervical cancer. Reviews in Medical Virology, 25 S1: 54-71. doi:10.1002/rmv.1824
Kobayashi, Takumi, Doff, Brianna L., Rearden, Rory C., Leggatt, Graham R. and Mattarollo, Stephen R. (2015) NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma. Oncoimmunology, 4 3: e990793-1-e990793-11. doi:10.4161/2162402X.2014.990793
Bergot, Anne-Sophie, Ford, Neill, Leggatt, Graham R., Wells, James W., Frazer, Ian H. and Grimbaldeston, Michele A. (2014) HPV16-E7 expression in squamous epithelium creates a local immune suppressive environment via CCL2- and CCL5- mediated recruitment of mast cells. PLoS Pathogens, 10 10: 1-11. doi:10.1371/journal.ppat.1004466
Leggatt, Graham R. (2014) Peptide dose and/or structure in vaccines as a determinant of T cell responses. Vaccines, 2 3: 537-548. doi:10.3390/vaccines2030537
McKee, Sara J., Mattarollo, Stephen R. and Leggatt, Graham R. (2014) Immunosuppressive roles of natural killer T (NKT) cells in the skin. Journal of Leukocyte Biology, 96 1: 49-54. doi:10.1189/jlb.4RU0114-001R
Bhat, Purnima, Leggatt, Graham, Matthaei, Klaus I. and Frazer, Ian H. (2014) The kinematics of cytotoxic lymphocytes influence their ability to kill target cells. PLoS One, 9 5: e95248.1-e95248.11. doi:10.1371/journal.pone.0095248
Mittal, Deepak, Kassianos, Andrew. J, Tran, Lee S., Bergot, Anne-Sophie, Gosmann, Christina, Hofmann, Janin, Blumenthal, Antje, Leggatt, Graham R. and Frazer, Ian H. (2013) Indoleamine 2,3-dioxygenase activity contributes to local immune suppression in the skin expressing human papillomavirus oncoprotein E7. Journal of Investigative Dermatology, 133 12: 2686-2694. doi:10.1038/jid.2013.222
Choyce, Allison, Yong, Michelle, Narayan, Sharmal, Mattarollo, Stephen R., Liem, Amy, Lambert, Paul F., Frazer, Ian H. and Leggatt, Graham R. (2013) Expression of a single, viral oncoprotein in skin epithelium is sufficient to recruit lymphocytes. PLoS One, 8 2: e57798.1-e57798.8. doi:10.1371/journal.pone.0057798
Fiorenza, Salvatore, Kenna, Tony J., Comerford, Iain, McColl, Shaun, Steptoe, Raymond J., Leggatt, Graham R. and Frazer, Ian H. (2012) A Combination of Local Inflammation and Central Memory T Cells Potentiates Immunotherapy in the Skin. Journal of Immunology, 189 12: 5622-5631. doi:10.4049/jimmunol.1200709
CD8 T cell tolerance to skin antigens/ skin tumours; combined immunotherapy/chemotherapy of tumours; and CD8 T cell avidity.
- Trafficking of T cells to cancerous skin
- Immunotherapy of skin tumours after lymphodepletion
- T cell function in normal and cancerous skin tissue