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 (ICI) targeting the PD-1 pathway have
transformed treatment of advanced renal cell carcinoma (RCC), but
mechanisms underlying therapeutic response remain largely unknown. Herein,
we perform transcriptomic analysis on RCC biospecimens from 102 patients
enrolled in a phase II clinical trial of frontline nivolumab (NCT03117309)
to investigate determinants of response to anti-PD1 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 have
superior clinical outcomes with nivolumab. Altogether, these analyses
contribute to a growing understanding of how the tumor microenvironment
drives ICI- resistance and propose possible therapeutic targets to
rationally overcome resistance to anti-PD1 monotherapy.