Characterization of Altered Immunity in Patients with Inflammatory Arthritis Induced by Immune Checkpoint Inhibitor Therapy

PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program for the career development of Dr. Sang Kim as an independent physician-scientist. The principal investigator is a physician-scientist who completed his PhD in immunobiology and his clinical rheumatology fellowship at Yale University. His career goal is to become an independent investigator studying rheumatic complications induced by immune-based cancer therapeutics. He proposes to expand his training in T cell and cancer immunology through an intensive training research experience under the mentorship of Dr. Roza Nurieva, a world leader with unparalleled intellectual and technical insight into the role of T cells in cancers and autoimmune diseases. In addition, because interactions of tumors and the host immune system are critical in development of immune-related adverse events (irAEs) induced by cancer immunotherapy, and because cutting-edge genomic technologies are a powerful tool in understanding the complex biology of the immune system, Dr. Kim will also have an opportunity to study cancer/functional genomics under the mentorship of Dr. Andrew Futreal (co-primary mentor), a world-renowned scientist in cancer genomics. The research objective of this proposal is to investigate mechanisms of arthritis associated with immune checkpoint inhibitor therapy (arthritis-irAE). Preliminary data for this proposal revealed the predominance of Th1 cell signatures in the patients with arthritis-irAE. In addition, Th17 cells were expanded in arthritis associated with combined PD-1 and CTLA-4 inhibitor therapy with steroid resistance. Furthermore, Dr. Kim observed that more CD4+ T cells were polarized into Th17 cells in skewing conditions in the presence of combined PD-1 and CTLA-4 inhibitors than in the presence of PD-1 inhibitor alone. From these results, Dr. Kim hypothesizes that Th1 cells play a critical role in the pathogenesis of arthritis-irAE and that Th17 cells are pivotal in steroid-resistant arthritis-irAE induced by combined PD-1 and CTLA-4 inhibitors. To address the hypothesis, Dr. Kim will investigate mechanisms leading to development of arthritis-irAE, with special focus on Th1/Tc1, Th17/Tc17, and regulatory T cells, and determine mechanism-driven biomarkers to predict development of arthritis-irAE, reflect arthritis disease activity, and predict steroid resistance. This proposal serves as a training vehicle for Dr. Sang Kim to become an expert in rheumatic complications induced by immune-based cancer therapy, an explosively emerging and challenging clinical entity in rheumatology.