Presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma 3574

Abstract Description There is a critical need to understand the mechanisms of response and resistance to PD-1 blockade in advanced renal cell carcinoma (RCC). Using scRNA-seq, we previously found increased tissue-resident ZNF683+ SLAMF7+ CD8+ exhausted T cells (T-exh-SLAMF7) in human RCC resistant PD-1 blockade in the HCRN GU16-260 trial. A T-exh-SLAMF7 gene expression signature (GES) was associated with worse clinical outcomes with PD-1 blockade in multiple validation cohorts. Here, through bulk RNA-seq of RCC biospecimens from 90 patients enrolled in this trial, we identified higher tertiary lymphoid structures (TLS) in patients responsive to PD1 blockade. Patients with complete/partial response had a higher (≥ median) TLS GES score compared to patients with progressive disease (p = 0.0004). Similarly, high TLS signature scores were associated with improved progression-free survival (PFS; p = 0.0032). We confirmed tumors with a high TLS GES score had a higher number of TLS detected by multiplex immunofluorescence (p = 0.028). Finally, we analyzed the interplay between TLS and tissue-resident exhausted CD8+ T cells. Patients with both high TLS and low T-exh-SLAMF7 GES scores had substantially improved PFS (p = 0.0052; 60.7% PFS at 12 months vs. 25.9% in all other patients). These findings support a paradigm where both high TLS and low T-exh-SLAMF7 cells are required for optimal response to PD-1 blockade in RCC. Future work will spatially interrogate the interplay between TLS and T-exh-SLAMF7 in RCC. Funding Sources Supported by DOD KCRP KC190130 / W81XWH-20-1-0533 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)