In the Oliaro laboratory, researchers investigate the regulation of cytotoxic lymphocytes – the immune cells that are responsible for the recognition and killing of cancer cells.
Our research focuses on investigating immune cell interactions with cancer cells, with a particular focus on immune synapse formation.
The regulation of cytotoxic lymphocyte activity in cancer
Cytotoxic lymphocytes (CLs), such as natural killer cells and cytotoxic T cells, are integral to immune protection against infection, and for the immunosurveillance of cancer. The anti-tumour cytotoxic activity of CLs relies on their formation of an immune synapse with tumour cells, which is fine-tuned by a range of co-signalling molecules that positively or negatively modulate lymphocyte activity. Alterations in the expression of their ligands on tumour cells can therefore impact strongly on lymphocyte function. Using cutting edge microscopy in combination with immunological techniques, this project investigates proteins that are critical for the recognition and killing of tumour cells by cytotoxic lymphocytes. This information is necessary if agents that target lymphocyte receptors and their ligands on tumour cells are to be utilised as an immunotherapy for cancer.
Novel therapies to enhance immune responses to treat cancer
This project focuses on a new class of drugs called ‘Smac-mimetics’, which specifically sensitise tumour cells to tumour necrosis factor-induced cell death. Interestingly, Smac-mimetics can also trigger inflammation, which can activate cells of the immune system and promote anti-tumour immunity. Smac-mimetics therefore represent an exciting new class of drugs for targeted cancer therapy. This project will investigate the potential of these drugs to enhance the anti-tumour immune response using models of cancer that clinically mimic disease progression and immune involvement in human patients. Smac-mimetics represent an exciting new class of anti-cancer drugs; however, it is essential to understand how they drive anti-tumour immunity in order to develop strategies to augment this potent effect to treat cancer. The results of this study have the potential to identify a novel and potent therapy that simultaneously promotes tumour cell death and anti-tumour immunity.
Investigating regulators of the cytoskeleton in immune cell polarity and function
The immune system is essential for protection against cancer and infection, but defects in immune cell function can lead to immune disorders such as autoimmunity and immunodeficiency disease. Immune cells are highly dynamic and must change shape rapidly in response to extracellular cues. However, the molecular and cellular regulation of immune cell polarity is not well understood. We recently discovered that a protein, DOCK8, is essential for the regulation of immune cell polarity and function. Significantly, humans suffering from a debilitating, and often lethal, severe combined immunodeficiency disease harbour biallelic DOCK8 mutations, highlighting the critical requirement of this protein in human immunity. This project will advance our knowledge of the cellular and molecular control of immune cell polarity in innate and adaptive immunity, which has implications for our understanding of immunodeficiency disease and the immunosurveillance of cancer.
Kearney CJ, Vervoort SJ, Hogg SJ, Ramsbottom KM, Freeman AJ, Lalaoui N, Pijpers L, Michie J, Brown KK, Knight DA, Sutton V, Beavis PA, Voskoboinik I, Darcy PK, Silke J, Trapani JA, Johnstone RW* and Oliaro J* (2018) Tumor immune evasion arises through loss of TNF sensitivity. Science Immunology May 18: 3(23)
Kearney CJ, Vervoort SJ, Ramsbottom KM, Freeman A, Peake J, Casanova J-L, Picard C, Tangye SG, Ma CS, Johnstone RJ, Randall KL and Oliaro J (2017). DOCK8 drives Src-dependent natural killer cell effector function. J Immunology doi: 10.4049/jimmunol.1700751
Kearney CJ, Lalaoui N, Freeman A, Ramsbottom KM, Silke J and Oliaro J (2017). PD-L1 and cIAPs Co-operate to Protect Tumors from Cytotoxic Lymphocyte-Derived TNF. Cell Death and Differentiation. 24(10):1705-17016
Kearney CJ, Ramsbottom KM, Voskoboinik I, Darcy PK and Oliaro J (2016). Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing. Oncoimmunology. 5(8): e1196308.
Ramsbottom KM, Sacirbegovic F, Hawkins ED, Kallies A, Belz G, Van Ham V, Haynes NM, Durrant M, Russell SM and Oliaro J (2015). Lethal Giant Larvae-1 deficiency enhances the CD8+ effector T cell response to antigen challenge in vivo. Immunol Cell Biol. 94(3): 306-11.
Ramsbottom KR, Hawkins ED, Shimoni R, McGrath M, Chan CJ, Russell SM, Smyth MJ and Oliaro J (2014). DNAM-1 deficient CD8+ T cells display immunological synapse defects that impair anti-tumour immunity. Journal of Immunol. 192(2): 553-7.
Hawkins ED*, Oliaro J*, Kallies A, Belz GT, et al. (2013). Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity. Nature Commun. 4: 1801. (* Equal first authors)
Randall KL, Chan SS-Y, Ma CS, Fung I, Arkwright PD, Suwairi WA, Picard C, Jouanguy E, Casanova JL, Lambe T, Cornall RJ, Russell S, Oliaro J*, Tangye SG*, Bertram E* and Goodnow CC* (2011). DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med. 208(11): 2305-20. (* Equal senior authors)