So new, so shiny, so powerful and so controversial!
Finishing high school and wondering what to study at university, a.k.a. what to do when I grew up, I became fascinated by the then emerging field of biotechnology. So new, so shiny, so powerful and so controversial!
Back in 1999, GMO crops were hotly debated and the course in biotechnology had just been added to the curriculum at the University of Milan. Reading Jeremy Rifkin’s “The biotech century” presenting biotechnology as the novel and revolutionary frontier of the upcoming century, I was captivated. I knew then I wanted to do something meaningful and helpful for people or maybe the planet, and this sounded like the right path. What I discovered along the way was that the details of cutting and pasting genes in and out of cells and organisms never really caught my strongest interest, but immunology did!
Immunology studies the complex network of cells and molecules that protects us from viruses, bacteria and cancer, and that sometimes focuses on the wrong target and attacks the body, causing autoimmune diseases, or harmless pollen, giving you allergies. Immune cells come in different shapes and styles, each with distinctive features and locations, and they act in coordination, as a well-trained army. There are macrophages that swallow bacteria and dying cells whole (their name means big eater), dendritic cells that carefully dissect pathogens to present them to T cells, as a skilful waiter fillets a fish, T cells that have different functions including killing virus-infected or cancer cells, B cells that produce antibodies (they are the cannon holders) and a few others. These cells are all so different and complex, undergoing several stages of maturation and differentiation, that most immunologists specialise in only one or two cell types, in one or few related diseases. I am a T cell person, with a touch of macrophage and dendritic cell expertise. Differently from the majority of my colleagues, I have been studying T cells in several settings - autoimmune diseases, allergy, influenza-virus infection- before starting investigating them in metastatic melanoma in 2018.
Why studying T cells in melanoma?
Australia and New Zealand are unfortunately the world capitals of melanoma, which is the 3rd most commonly diagnosed cancer nationally in 2020. While localised melanoma, mostly in the skin, has a very good survival rate, the capacity of melanoma to metastasise to almost all the organs, most commonly the lymph nodes, makes it life-threatening.
The presence of T cells in and around the tumour predicts better survival, in particular tissue resident memory cytotoxic T cells (TRM), so named because they are localised in the tissues (tissue resident), they can kill other cells (cytotoxic), including melanoma cells, and have been previously activated and now persist in the body (memory). TRM have been identified only 10 years ago and they have been shown to protect mice from melanoma and to be correlated with longer survival in humans. Their function in human metastatic melanoma is still unknown and that is what my colleagues and I have been working on in the past 2 years in the HITRL group. We hypothesise that the TRM population is enriched with T cells that can recognise the tumour as a target cell to kill. We have so far been able to show this in one patient affected by a rare case of mucosal metastatic melanoma and we are testing it on several more. We are very fortunate to be able to use several state-of-the-art technologies that are available at Peter Mac, such as the flow cytometry core to sort the T cells, the microscopy facility to perform multiplex immunohistochemistry, to reveal where the TRM are in the tumour, and the genomics core to perform single cell RNA sequencing.
Why then is the immune system incapable to kill the cancer before it grows and spreads?
Tumour cells have the capacity to evolve so sneakily to hide from the immune system or to block it in different ways, and that’s when cancer arises.
Several approaches have been tested to boost T cell capacity to kill cancer cells and so far the most effective treatment arrived in the clinics 5 years ago, the immune checkpoint blockers (ICB). ICB revolutionised the treatment of melanoma and allowed much longer survival to metastatic melanoma patients compared to previous treatment.
ICB are antibodies that block proteins on immune cells that stop them from attacking melanoma cells. While they boost the immune system’s response against melanoma cells, they can also cause side effects, including inducing the immune system to attack other healthy parts of the body, such as the heart or colon, causing severe side effects. This illustrates the complexity and double-edged sword that the immune system is! Moreover, ICB only work in about 50% of metastatic melanoma patients.
The task of distinguishing responders from non-responders prior to administering the drugs, is being tackled intensely by the scientific community. Part of our project is addressing this problem by asking the question of which subset of T cells are responsible for the response to ICB. We think it’s TRM but science will have the last word.
Figure legend: Immunohistochemistry of a tumour. Melanoma cells in grey are surrounded by different T cell populations, including TRM in pink.
Dr Angela Pizzolla is a Postdoctoral Researcher in the Human Immunology Translational Research Laboratory under the supervision of A/Prof Paul Neeson, which is part of the Cancer Immunology Research division within the Peter Mac Research Faculty. Her expertise includes immunology, T cell biology, mouse models of diseases and more recently human melanoma immunology.
Dr Angela Pizzolla can be contacted by:
Email: [email protected]
Google Scholar: https://scholar.google.com/citations?user=PFciApwAAAAJ&hl=en