Data 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

• DOI: 10.1158/1078-0432.c.7077690
• Publication Date: 2024-02-16T08:20:34Z
• Authors: Thomas Denize; Opeyemi A. Jegede; Sayed Matar; Nourhan El Ahmar; Destiny J. West; Emily Walton; Aseman Sheshdeh B...; 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

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