Presence of Tertiary Lymphoid Structures and Exhausted Tissue-Resident T Cells Determines Clinical Response to PD-1 Blockade in Renal Cell Carcinoma

Immune checkpoint inhibitors targeting the PD-1 pathway have transformed treatment of advanced renal cell carcinoma (RCC), but mechanisms underlying the therapeutic response remain largely unknown. In this study, we perform transcriptomic analysis on RCC biospecimens from 102 patients enrolled in a phase II clinical trial of first-line nivolumab (NCT03117309) to investigate determinants of response to anti–PD-1 monotherapy. Through bulk analysis, we identify an enrichment of genes associated with tertiary lymphoid structures (TLS) in responding patients. Using single-cell transcriptomics and external cohort validation, we identify a population of tissue-resident (ZNF683⁺ SLAMF7⁺) exhausted CD8⁺ T cells enriched in patients with poor clinical outcomes. Integrating these findings, we find tumors with high TLS and low tissue-resident exhausted CD8⁺ T cells that have superior clinical outcomes with nivolumab. Altogether, these analyses contribute to a growing understanding of how the tumor microenvironment drives immune checkpoint inhibitor resistance and propose possible therapeutic targets to rationally overcome resistance to anti–PD-1 monotherapy. Significance: We describe a paradigm wherein combined high TLS and low tissue-resident exhausted CD8⁺ T cells are required for optimal response to PD-1 blockade in RCC. This analysis identifies key determinants of response to PD-1 blockade in advanced RCC and suggests avenues for future immune modulation through rational combination therapy strategies.