Abstract

Immune checkpoints are regulators of immune activation that can be triggered to suppress the immune response against tumours. Immune checkpoint inhibitors (ICIs) have shown efficacy in a variety of cancer types, but in the majority of cancer types only a minority of patients respond. The aim of this Ph.D. was to examine mechanisms of immune response against breast cancer cells by examining immune relevant treatments. The monoclonal antibody trastuzumab is approved to treat HER2+ breast cancer. Trastuzumab can engage certain cells of the immune system to kill cancer cells through antibody-dependent cell-mediated cytotoxicity (ADCC). The ability of cancer patients’ immune cells to engage in trastuzumab-mediated ADCC was determined in vitro using peripheral blood mononuclear cell (PBMC) samples from the ICORG 10-05 clinical trial. The PD-1 receptor and its cognate ligand PD-L1 are an immune checkpoint axis that is currently under investigation in the clinic. Protocols to examine the impact of ICIs in vitro are limited. An assay was developed using immune cell populations isolated from healthy volunteers that this sample cohort could be utilised for this purpose. A link between EGFR and PD-L1 expression was discovered in a panel of HER2-targeted therapy resistant breast cancer cell lines. The molecular mechanisms underlying this link suggest that there is value in the rational combinations of EGFR/HER2 inhibitors and ICIs. Adenosine is a metabolic checkpoint in the tumour microenvironment. Modulation of adenosine receptor 2A (A2AR) resulted in altered trastuzumab-mediated ADCC in treatment-naïve HER2+ breast cancer in vitro, suggesting a potential therapeutic role for A2AR modulation in breast cancer. A hypothesis to explain the efficacy of ICIs in heavily pre-treated cancer patients was explored. The study suggests that immune-related gene sets have significantly lower rates of amplification and deletion and recurrent point mutation versus commonly targeted cancer-related genes. This suggests the targets of ICIs are more genetically stable than commonly targeted cancer-related pathways.