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)

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Journal
The Journal of Immunology
Published
2025-11-01
DOI
https://doi.org/10.1093/jimmun/vkaf283.1362
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
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article

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

Lena Vanessa Wirth, Kelly Street, David F. McDermott, Miya B. Hugaboom et al.
The Journal of Immunology
Cancer Immunotherapy and Biomarkers
article

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

Lena Vanessa Wirth, Kelly Street, David F. McDermott, Miya B. Hugaboom, Thomas Denize, David Braun, Elizabeth R. Plimack, Sayed Matar, Naomi B. Haas, Sabina Signoretti, Catherine J. Wu, Mehmet Asım Bilen, Destiny West, Toni K. Choueiri, Michael B. Atkins, Valisha Shah, Nourhan El Ahmar, Robert Alter, Mark N. Stein, Nicholas R. Schindler, Jacob Peter Zaemes, Jeffrey A. Sosman, Michael E. Hurwitz, Opeyemi A. Jegede, Neil G. Ruthen, Varunika Savla, Hans J. Hammers
article en

Abstract

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)

The Journal of ImmunologyVol. 214(Supplement_1)
University of Southern California (US), Brigham and Women's Hospital (US), Fox Chase Cancer Center (US), Hackensack University Medical Center (US), Harvard University (US), Emory University (US), Georgetown University (US), Columbia University Irving Medical Center (US), Hadassah Medical Center (IL), Georgetown University Medical Center (US), Yale University (US), Massachusetts General Hospital (US), Dana-Farber Cancer Institute (US), Temple University Health System (US), University of Pennsylvania Health System (US), Southwestern Medical Center (US), The University of Texas Southwestern Medical Center (US)
U.S. Department of Defense, Pancreatic Cancer Action Network, National Institutes of Health
Openalex Percentile: Top 52%
Cancer Immunotherapy and Biomarkers
DOIOpen Access PDFOpenAlex
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