Jane Oliaro

Cytotoxic lymphocytes, such as T cells and natural killer cells, are key to our immune defence against cancer. A number of immunotherapy approaches, such as checkpoint blockade, target cytotoxic lymphocytes in order to boost their anti-cancer activity. Despite the expanding use of checkpoint blockade therapies in the clinic, a limitation to this approach is that the number and functionality of lymphocytes can vary significantly within tumours, leading to variation in the proportion of patients who respond positively to immunotherapy. As such, approaches designed to dissect the factors governing cytotoxic lymphocyte function in cancer are urgently required to design effective combination therapies that promote anti-cancer immunity and improve immunotherapy responses. To address this, the laboratory uses whole genome loss of function screening combined with immune-based assays to identify novel regulators of lymphocyte activity and fate that can be targeted therapeutically.

The development of acquired cancer cell resistance to immunotherapy is a significant and clinically relevant problem. Understanding the mechanisms by which cancer cells avoid our immune system is essential for the rational design of new treatments to combine with immunotherapy and overcome resistance. To address this, we use a range of immunological techniques, combined with genetic screening and preclinical models, to identify the genes and pathways that determine if a cancer cell will be sensitive or resistant to immunotherapy. We focus on treatments that may overcome resistance to checkpoint blockade in melanoma, breast and colorectal cancer or to CAR T cell therapy in haematological cancers. This research also has the potential to identify new therapeutic targets and markers of resistance that correlate with clinical response to predict treatment outcomes.

Given the dependence of immunotherapy on the presence of cytotoxic lymphocytes within tumours, agents that can synergise with immunotherapies to create a more inflammatory microenvironment and promote the infiltration of lymphocytes into the tumour site are of great interest. A class of anti-cancer drugs, called smac-mimetics (SMs), are the ideal candidates for this, as they can induce direct tumour cell death while also triggering the secretion of inflammatory chemokines and cytokines that can attract immune cells into the tumour site. SMs also sensitise cancer cells to cell death mediated by the cytokine, TNF, which is produced by lymphocytes upon tumour recognition. Our research investigates the role of TNF in anti-tumour immunity and response to immunotherapy, and the potential of SMs to enhance the immune response and increase the number of patients and cancer types that respond to checkpoint blockade or CAR T cell therapy.