Characterization of anti-cancer immune response associated with immune-related adverse events in patients with kidney cancer.

711 Background: Some reports showed promising clinical efficacy among patients who discontinued immune checkpoint inhibitors (ICIs) due to immune-related adverse events (irAEs). In this study, we aimed to characterize T cell receptor (TCR) repertoire repertoire in peripheral blood mononuclear cells (PBMCs) before and after ICI treatment, and at the onset of irAE for understanding of irAE-provoked anti-cancer immune responses. Methods: We collected metastatic tumor tissues and peripheral blood samples from 54 patients with advanced kidney cancer before anti-programmed cell death protein 1 (PD-1) treatment and 1 month after treatment initiation. Furthermore, we applied a next-generation sequencing approach to characterize TCR repertoires using tumor tissues and PBMCs. Results: The number of irAEs was significantly higher in responder for nivolumab (p < 0.0001). We also confirmed that irAE present patients had better progression-free survival and overall survival when compared to irAE absent patients (p=0.0010 and p=0.011, respectively). TCR repertoire analysis revealed that diversity index for TCR alpha and beta in irAE present patients were significantly decreased at 1 month after nivolumab, indicating expansion of certain T cell clones even in PBMCs after nivolumab. We also examined morishita index to measure T cell similarity between pre- and post nivolumab samples. As a result, irAE present patients had significantly lower similarity than irAE absent patients, indicating a larger change in the T cell clones, and inducing newly expanded T cell clones in post-nivolumab PBMC samples. Importantly, irAE present patients had significantly higher numbers of peripheral T cell clones shared with metastatic tumor-infiltrating T cells than those in irAE absent patients at 1 month after nivolumab (as per the 100 most abundant T cell clonotypes in the peripheral blood; p=0.038). Conclusions: Our findings revealed that a certain number of irAE-provoked T cell clones can also circulate systemically and attack tumor cells in distant regions, leading to durable response in the patients with irAEs.