American Association for Cancer Research
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Figure S1 from PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti–PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients

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journal contribution
posted on 2024-02-16, 08:20 authored by Thomas Denize, Opeyemi A. Jegede, Sayed Matar, Nourhan El Ahmar, Destiny J. West, Emily Walton, Aseman Sheshdeh Bagheri, Varunika Savla, Yasmin Nabil Laimon, Saurabh Gupta, Sai Vikram Vemula, David A. Braun, Kelly P. Burke, Paul J. Catalano, Gordon J. Freeman, Robert J. Motzer, Michael B. Atkins, David F. McDermott, Arlene H. Sharpe, Toni K. Choueiri, Sabina Signoretti

Figure S1


National Cancer Institute (NCI)

United States Department of Health and Human Services

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Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3−LAG-3− tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors. PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3−LAG-3− cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus. PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3−LAG-3− cells has higher predictive value.