Cellular Immunity Projects

Cellular Immunity Projects - Research at Peter Mac

INNATE CYTOKINE NETWORKS AND INFLAMMATION

Supervisors: Dr. Dan Andrews and Prof. Mark Smyth

Innate immune cells include NKT and gamma delta T cells. NKT cells can produce significant quantities of cytokines very rapidly, making them potent regulators of immune responses during infection and cancer. Subsets of NKT cells exist, which have been ascribed different properties. These subsets produce different cytokines upon stimulation, which is thought to be how NKT cells mediate diverse functions. Similarly to NKT cells, gamma delta T (gdT) cells are known to play a significant role in innate immunity. The cytokine producing capabilities of gdT cells is now becoming more widely recognized as is the role these can play in shaping immunity.

We are utilizing several models of inflammation and sepsis in mice to determine the key cytokine networks regulated by these unique innate lymphocyte subsets and their relationship to NK cells. Interest is focused upon IL-1 family members and IL-17, a pro-inflammatory cytokine whose production was originally ascribed to a lineage of helper T cells termed Th-17. Significantly, septic shock is diagnosed in approximately 750,000 patients/year in North America and Europe and around 31% of these patients die making understanding of the molecular mechanisms operating during inflammation of significant importance.

We are seeking an Honours student to pursue a project focused on these cellular interactions and their relevance to inflammation. Students will have access to excellent infrastructure and will learn skills in mouse experimentation, leukocyte isolation and transfer, multi-color flow cytometry, cytometric bead array, ELISA, and basic molecular techniques.

Reference relevant to this project:
Lyakh, L et al. (2008) Immunol Rev. 226:112.

For more information about this project, contact:

Dr Daniel Andrews

+61 (0)3 9656 1752

daniel.andrews@petermac.org

THE IDENTITY, ROLE AND FUNCTION OF IMMUNE CELLS AT SITES OF METASTASIS IN BREAST CANCER

Supervisors: Dr. Andreas Moeller & Prof. Mark Smyth

The main cause of morbidity in breast cancer patients is caused by the spread of the diseases to distant sites, commonly called metastasis. At the original site of the primary tumour as well as at metastatic sites, tumour cells are interacting with the surrounding environment. Immune cells are key mediators of anti-tumour and pro-tumour functions at both the primary and metastatic site. While the role of monocyte derived cells at the primary site of breast cancer is slowly being understood there is very little known about the role and composition of immune cells at metastatic sites. We have generated a unique breast cancer model, utilizing fluorescently marked immune and tumours cells, to assess the immune cell infiltrate at metastatic sites in breast cancer. We found that immune cell infiltration into metastatic sites is directed and orchestrated by primary tumours. These immune cells generate a microenvironment aiding further metastatic tumour progression.

In this project, bone marrow chimeras and orthotopic breast cancer models will be used to determine the composition of the immune cell infiltrate into the metastatic sites as well as their functions. Using FACS and Immuno-histology, the immune cell lineages will be investigated in great detail. Isolated immune cells, which are induced by tumours to populate the metastatic site, will be assessed for their cytokine production. Furthermore, the frequency of metastasis will be assessed in experiments where the immune cell lineages which populate the metastatic site have been ablated. These experiments will provide an insight into the metastatic progression of breast cancer and will be the first of their kind. Ultimately the goal is to understand the identity, role and function of immune cells at the metastatic site and explore the potential to use this information to reduce metastatic tumour burden in breast cancer patients. PhD students will have access to unique reagents/mice and excellent infrastructure and will acquire skills in mouse tumour model experimentation, immune cell isolation, multi-colour flow cytometry, IHC, and other basic cellular immunology techniques.

For more information on this project, contact:

Dr Andreas Moeller

+61 (0)3 9656 1287

andreas.moeller@petermac.org

Professor Mark Smyth

+61 (0)3 9656 3728

mark.smyth@petermac.org

THE ROLE OF DC IN TUMOUR THERAPIES

Supervisors: Dr. Nicole Haynes & Prof. Mark Smyth

The therapeutic efficacy of anticancer chemotherapies may depend on the capacity of dendritic cells (DC) to present antigens from dying cancer cells and to prime tumor-specific interferon-g-producing T lymphocytes. Recently we have shown that some anticancer chemotherapies that are successful in immunocompetent mice are inefficient against tumors established in mice defective in various components of the NLRP3-dependent caspase-1 activation complex ("inflammasome"). Other studies of ours illustrate the optimal therapeutic efficacy of agonistic antibodies to the TRAIL death receptor requires host CD11c leukocyte function. We are offering PhD studies to now systemically determine an immune signature of dying tumour cells and the role of various myeloid cell populations in mediating the anti-tumour activity of conventional and novel cancer therapies. Various gene-targeted mice specifically deficient in various subsets of DC or molecules of the inflammasome will be available. Students will have access to excellent infrastructure and will acquire skills in mouse tumour model experimentation, leukocyte isolation, multi-color flow cytometry, apoptosis and phagocytosis assays, and other basic cellular immunology techniques.

For more information on this project, contact:

Professor Mark Smyth

+61 (0)3 9656 3728

mark.smyth@petermac.org