Skip to main content
Dryad

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

Hugaboom, Miya1; Wirth, Lena1; Street, Kelly2; Ruthen, Neil3; Jegede, Opeyemi4; Schindler, Nicholas1; Shah, Valisha4; Zaemes, Jacob5; El Ahmar, Nourhan6; Matar, Sayed6; Savla, Varunika6; Choueiri, Toni4; Denize, Thomas6; West, Destiny6; McDermott, David7; Plimack, Elizabeth8; Sosman, Jeffrey9; Haas, Naomi10; Stein, Mark11; Alter, Robert12; Bilen, Mehmet13; Hurwitz, Michael1; Hammers, Hans14; Signoretti, Sabina6; Atkins, Michael5; Wu, Catherine4; Braun, David1

Published Feb 20, 2025 on Dryad. https://doi.org/10.5061/dryad.dv41ns28r

Data files

Feb 20, 2025 version files 463.26 MB

Click names to download individual files

Abstract

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.