| dc.description.abstract | A crucial challenge in the care of cancer patients is identifying which treatment is most likely to benefit, and least likely to harm, each individual cancer patient. Herein, I present two projects: one which seeks to understand one of the most harmful toxicities of anti-cancer immunotherapy, and the second which aims to identify which patients are likely to have long term benefit from chemotherapy. First, we developed a murine model which recapitulates the clinical and pathologic features of immune checkpoint inhibitor associated myocarditis, the immune related adverse event with the highest mortality. Using this model, we found that CD8+ T cells are key drivers of myocarditis and that the most clonal CD8+ T cells recognize alpha-myosin. We found that alpha-myosin peptides could drive clonal T cell expansion from blood T cells in humans. In immunotherapy associated myocarditis patients, the alpha-myosin expanded T cell receptors (TCRs) overlap with TCRs found in inflamed heart tissue, suggesting that alpha-myosin may be an important autoantigen in humans. Second, we aimed to understand the effects of chemotherapy on local and systemic immunity in breast cancer, with a goal of developing blood-based biomarkers. We found differences in gene expression and cell type abundance in the blood, following treatment with neoadjuvant chemotherapy (NAC), predicted response to NAC and breast cancer recurrence. In particular, high levels of monocytes following NAC were associated with good outcomes. Herein, we have provided mechanistic insight into a deadly toxicity and helped further the goal of minimally-invasive biomarker development. | |
