Mechanisms of Immune Checkpoint Inhibitor-Associated Thrombosis
Thrombosis, the development of abnormal blood clots, is the second most common cause of death in cancer patients. The risk of cancer-associated thrombosis (CAT) is increased with certain types of cancer and cancer treatments, including chemotherapy. Over the last decade, the use of cancer immunotherapy, particularly immune checkpoint inhibitors (ICI), has emerged as a mainstream cancer treatment. ICI block natural pathways used by the tumor to shield itself from attack by the immune system. However, since immune attack induced by ICI cannot be directed specifically toward the tumor, normal tissues and organs may be affected as well, leading to immune related adverse events (irAE) that may involve muscles, heart, and hematologic systems, among others. We have described a serious and common irAE overlooked until recently–thrombosis, which we refer to as ICI-associated thrombosis (IAT). In our series from Taussig Cancer Institute, IAT occurred in 24% of ICI-treated patients, and was associated with decreased survival. However, there is no information available concerning how ICI cause thrombosis; developing a better understanding of these mechanisms will be essential for continued development of ICI and lead to better patient outcomes. We propose that IAT develops due to direct interactions of ICI with blood and vascular cells, leading to activation of these cells and causing them to enhance blood clotting. On top of the preexisting inflammatory and prothrombotic milieu of cancer, these interactions cause thrombosis. Here, we propose to use human blood cells, patient samples, and a mouse model of IAT to test this hypothesis.
The goal of my study is to better understand the mechanisms leading to blood clots in cancer so that we can prevent them before they happen.