In the Oliaro laboratory, we use the latest technology to dissect the complex interplay between the immune system and cancer, and apply this knowledge to guide innovative immunotherapy approaches for the treatment of cancer.
Recent breakthroughs in our understanding of anti-tumour immune responses has led to the development of an expanding generation of cancer immunotherapies, and a revolution in the treatment of cancer. Immunotherapy, such as checkpoint blockade, is designed to promote the immune response to cancer, but the clinical benefit is limited to a subset of patients. As such, there is a concerted research effort to identify additional therapeutic targets on immune cells, and mechanisms of cancer cell immune evasion.
Our laboratory has made a significant contribution to the understanding of anti-tumour immunity and resistance mechanisms through the integration of whole genome CRISPR screening and functional immune-based assays. Through this approach we can identify the key genes involved in the regulation of immune cells during cancer, and the genes and pathways involved in cancer cell immune evasion and resistance to immunotherapy. These approaches also provide a unique opportunity to identify biomarkers that predict patient response, and inform the rational design of new combination immunotherapies to improve patient response rates and overcome resistance.
The regulation of cytotoxic lymphocyte activity in cancer
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.
Cancer cell resistance to immunotherapy
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.
Novel therapies to enhance immunotherapy responses to treat cancer
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.
Lelliott EJ, Kong I, Zethoven M, Ramsbottom KM ... Johnstone RW, Oliaro J, Sheppard KE, Kearney CJ, Vervoort SJ (2021) CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory. Cancer Discovery DOI:10.1158/2159-8290.CD-20-1554
Kearney CJ, Vervoort SJ, Ramsbottom KM, Todorovski I, Lelliott EJ, … Oliaro J* and Johnstone RW* (2021) SUGAR-seq enables simultaneous detection of glycans, epitopes and the transcriptome in single cells. Science Advances 7(8): eabe3610 *Equal senior authors
Lelliott EJ, Mangiola S, Ramsbottom KM, … McArthur GA, Oliaro J* and Sheppard KE* (2021) Combined BRAF, MEK and CDK4/6 inhibition depletes intratumoral myeloid populations critical for T cell immunity in melanoma. Cancer Immunology Research 9(2): 136 *Equal senior authors
Freeman AJ, Vervoort SJ, Ramsbottom KM, Kelly MJ, Michie J, Pijpers L, Johnstone RW, Kearney CJ and Oliaro J (2019) Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion. Cell Reports 28 (11): 2784
Michie J, Beavis PA, Freeman AJ, Vervoort SJ, Ramsbottom KM, Narasimhan V, Lelliott EJ, Lalaoui N, Ramsay RG, Johnstone RW, Silke J, Darcy PK, Voskoboinik I, Kearney CJ and Oliaro J (2019). Antagonism of IAPs enhances CAR T cell efficacy. Cancer immunology Research 7 (2): 183
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 3 (23): 3451
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
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