Adoptive T Cell Therapy of Breast Cancer: Defining and Circumventing Barriers to T Cell Infiltration in the Tumour Microenvironment

In the era of personalized cancer treatment, adoptive T cell therapy (ACT) shows promise for the treatment of solid cancers. However, partial or mixed responses remain common clinical outcomes due to the heterogeneity of tumours. Indeed, in many patients it is typical to see a response to ACT in one tumour nodule, while others show little or no response. Thus, defining the tumour features that distinguish those that respond to ACT from those that do not would be a significant advance, allowing clinicians to identify patients that might benefit from this treatment approach.;The first chapter of this thesis provides the necessary background to understand the principals behind and components of ACT. This chapter also offers selected historical advances contributing to the current state of the field. The second chapter introduces a novel murine model of breast cancer developed to investigate the tumour-specific mechanisms associated with immune evasion in an ACT setting. The third chapter describes the in vivo characterization of mammary tumour cell lines derived from our mouse model that reliably showed complete, partial or no response to ACT. Using these cell lines, we were able to characterize in vivo tumour-specific differences in cytotoxic T cell trafficking, infiltration, activation, and proliferation associated with response to ACT. In the fourth chapter, we used bioinformatics approaches to develop a preliminary predictive gene signature associated with response to ACT in our mammary tumour model. We used this signature to predict outcome and then test a number of murine mammary tumours in vivo, with promising results, wherein 50% of tumours responded to ACT as predicted based upon gene expression. Thus, using an innovative model for breast cancer, these results suggest that there are tumour-specific features that can be used a priori to predict how a tumour will respond to adoptive T cell therapy. Importantly, these findings might facilitate the design of immunotherapy trials for human breast cancer.