Determine the Mechanism Behind Immune-Related Adverse Events Associated with Checkpoint Inhibitors
As many as 25% of the patients that receive anti-PD-1 treatment also develop immune-related adverse effects, particularly autoimmunity. As such, understanding the mechanisms which control immune-tolerance breakdown remains a critical goal. These mechanisms lead to excessive inflammation in cancer patients undergoing treatment, and knowledge of their function is crucial for both the identification of the predictive biomarkers for inflammatory toxicities and the development of a new generation of safer immunotherapies.
Immune checkpoint inhibitors can lead to the development of inflammation in many organs. The treatment of tumors with anti-PD-1 or anti-PD-L1 antibodies increases the activation of tumor infiltrating cytotoxic T cells and leads to tumor cell death. These activated T cells with decreased function of the PD-1 checkpoint pathway have also been observed in peripheral circulation and have been isolated from inflamed organs in patients with immune related adverse events.
We study the ways in which PD-1 blockade reshape homeostatic T cell responses, making use of single-cell RNA sequencing. These findings will fill a critical gap in our understanding of the molecular complexity within the T cell repertoire transition during the development of autoimmunity.