IMPROVING OUTCOMES FOR CANCER IMMUNOTHERAPY

Cancer is the leading cause of death in Canada and one of the leading causes of death worldwide. Conventional cancer therapies such as chemotherapy often include severe side effects that can decrease the quality of life of patients undergoing treatment. Immunotherapy is designed to harness the host immune response and enhance its ability to seek out and kill cancer cells. Immunotherapy has gained traction in the past decade due to its improved safety and efficacy over conventional cancer therapies. However, there is room for improvement as most patients fail to respond to immunotherapy. The work described in this dissertation involves the development of therapeutic combination platforms that are designed to improve upon immunotherapy outcomes. Murine tumor models were used to develop a better understanding of biological processes associated with therapeutic efficacy. These findings can be used for the development of therapeutic strategies that can further improve the efficacy of cancer immunotherapy. Cancer immunotherapy has demonstrated immense promise in the past decade. Immune checkpoint therapy has shown unprecedented responses in many cancers; however most patients fail to respond to checkpoint therapy. This highlights the need to develop a better understanding of factors in the tumor microenvironment that can influence therapeutic outcomes. In this body of work, we have utilized oncolytic viruses (OVs) to enhance immunogenicity in the tumor and study the cellular mechanisms that enable a therapeutic response. We utilize a combination of OVs and low dose chemotherapy to further sensitize murine models of mismatch repair-deficient colorectal cancer to checkpoint therapy. Using a Clariom S transcriptome assay we found that the combination induced gene signatures associated with the recruitment and activation of myeloid subsets. When we assessed tumor infiltrates, we found that the combination induced the chemoattraction of several myeloid subsets, including type I conventional DCs (cDC1s) which are known for their role in antigen presentation. Using Batf3-/- mice, we demonstrated that the therapeutic efficacy of our combination platform was dependent on the presence of cDC1s. In this dissertation, we also studied the role of OV-induced type I IFN (IFNI) in enabling or suppressing antitumor immunity. We found that OVs induced the upregulation of PD-L1 in an IFN-I-dependent manner in cancer cells and circulating immune cells. Inhibition of IFN-I signaling using an anti-IFNAR monoclonal antibody partially prevented OV-induced upregulation of PD-L1. Furthermore, the combination of OV and v | P a g e IFNAR blockade enhanced the effector functions of tumor-specific T cells and led to better tumor control compared to OV monotherapy. Altogether, these findings demonstrate that OVs can be an effective agent for enhancing immunogenicity in the tumor and promoting the infiltration of inflammatory myeloid subsets. By combining OVs with checkpoint or IFNAR inhibitors, we prevent the onset of immunosuppression and enable a favorable therapeutic response. Thesis Doctor of Philosophy (Medical Science)