Immune Imaging

Group Head: Professor Wolfgang Weninger

The Immune Imaging program studies basic questions related to cancer and infectious diseases. We are using cutting-edge microscopy techniques to determine how the immune system fights tumours and microbes. We are further interested in determining the role of cancer stem cells in the development of melanoma and the effects of targeted therapies on these cells in vivo.

The principle approach of the Immune Imaging program is the use of a state-of-the-art imaging technique called multi-photon microscopy. This technology allows for visualisation of fluorescently-tagged cells and molecules within the context of living tissues. We can now study the dynamics of cell movements and interactions at a level of resolution that has not been reached before. Using this approach, the laboratory is investigating fundamental questions related to skin and pulmonary infections as well as cutaneous tumours.

One interest is the visualisation of white blood cell (leukocyte) behaviour within living tissues. Leukocytes are responsible for the recognition and destruction of invading microbes, such as viruses, bacteria and parasites, as well as tumour cells. Multi-photon microscopy enables us to study how microbes and tumour cells are detected and destroyed by leukocytes in real time in the context of intact tissues.

A second interest relates to the pathogenesis of melanoma, the most aggressive and often therapy-resistant form of skin cancer with a particularly high incidence in Australia. The resistance of metastatic melanoma to conventional chemotherapy may be explained by the existence of a recently discovered multi-drug resistant population of cells, called melanoma stem cells (MSC). Our aim is to use multi-photon microscopy in order to characterise the biology of MSC both in three-dimensional melanoma models in vitro as well as in mouse models in vivo.

Research focus

Role of dendritic cells in skin infections
Dendritic cells, including those in the skin, act as sentinels for intruding pathogens. We have recently developed an intravital multi-photon microscopy model that allows us to directly visualise these cells in intact skin. Using a Leishmania parasite and a Herpes simplex virus model, we are investigating how dendritic cells behave during the early phase of immune responses, and how pathogens are recognised and transported from the skin to draining lymph nodes. These studies have implications for the development of vaccines against infections.

Interplay of innate and adaptive immune cells during influenza virus infection
Influenza is an acute febrile respiratory illness caused by influenza virus infection and may trigger potentially life-threatening complications especially in the young and elderly. Immunity against influenza virus involves integration of the innate and adaptive immune system. However, we currently have a poor understanding as to how the interactions between the cellular components of the anti-influenza immune response are orchestrated in space and time.

We are making use of intravital multi-photon microscopy to study how innate immune cell subsets induce the activation of antigen specific T cells in draining lymph nodes of the lung during infection. In-depth insight into this process is not only important for increasing our knowledge of regulatory pathways of anti-viral immunity, but may, in the long-term, lead to the development of improved vaccine strategies against this important disease.

Mechanisms of T cell migration and interactions in tumours
Tumour cell-host cell interactions are critical determinants for the progression of cancer. Of particular importance are cytotoxic T cells, as they may recognise and destroy tumour cells. How T cells navigate within the tumour microenvironment, how they interact with cancerous cells, as well as their overall contribution to the tumour micromilieu is not well understood.

The project's long-term goal is to define the cellular and molecular cues responsible for the guidance of tumour infiltrating T cells (TIL) through the tumour stroma and mediation of their communication with cancerous cells. We hypothesise that the quality of TIL migration and interactions with target cells determines whether a tumour is destroyed or grows unimpeded. To test our hypothesis, we will employ multi-photon microscopy in our recently-developed subcutaneous tumour model.

Our experiments will provide mechanistic insights into the events leading to tumour cell destruction or tumour immune evasion. Therefore, these studies have important implications for the optimisation of immuno-therapeutic strategies that aim to target cancer.

Role of melanoma stem cells in melanomagenesis
We are testing the hypothesis that melanomas recur after chemotherapy because MSC are chemo-resistant and can reinitiate tumour growth.

The central idea of our current work is that both MSC and melanoma tumour cells need to be targeted simultaneously to achieve complete remission of melanoma. We have developed three-dimensional melanoma culture models, which recreate the correct interactions of the melanoma with its tumour microenvironment and thus can predict the effects of drugs on the tumour in a much better way than conventional two-dimensional cell culture. These models are used in combination with in vivo mouse models and multi-photon microscopy to study the interactions of MSC and melanoma cells with their microenvironment.

We are further assessing the effects of chemotherapeutic drugs on these cells. From these experiments we hope to develop novel therapeutic concepts for this devastating disease.