DEVELOPING NATURAL KILLER T CELL BASED TOOLS AND STRATEGIES FOR TARGETING BREAST CANCER

Abstract

Natural killer T cells are a rare population of immune-regulatory lymphocytes which have been implicated in tumor control. However, the benefit of NKT cell activation therapy in metastatic breast cancer remains poorly understood. The major focus of this work was to examine the potential role of NKT cell activation in a murine model of post-surgical breast cancer metastasis. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with α-GalCer-loaded dendritic cells. This therapeutic approach decreased tumor burden, prolonged survival, and decreased the frequency and activity of myeloid derived suppressor cells. However, survival was not enhanced by additional dendritic cell treatments. This led us to investigate whether we could augment therapeutic outcomes by combining NKT cell activation with chemotherapy or oncolytic virus therapy, both capable of inducing immunogenic cell death. Combining cyclophosphamide or gemcitabine with NKT cell activation therapy significantly enhanced survival, with surviving mice exhibiting attenuated tumor growth following a second tumor challenge. Similarly, combining NKT cell activation therapy with oncolytic vesicular stomatitis virus also significantly enhanced therapeutic outcomes. Collectively, our findings demonstrate that NKT cell activation therapy as a monotherapy, or in combination with chemo- or viro-therapy, can protect mice from post-surgical breast cancer metastasis.