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.

PD-1 expression on CD8+TIM-3-LAG3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC). Since PD-1 signaling inhibition in regulatory T cells (Tregs) 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 et al, 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 versus 5.78 months; p=0.021), shorter OS (18.1 versus 27.7 months, p=0.013) and marginally lower ORR (12.5% versus 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 ratio experienced shorter PFS (3.48 versus 9.23 months, p<0.001), shorter OS (18.14 versus 38.21 months, p<0.001) and lower ORR (15.69% versus 40.00%; p=0.009). Compared to the individual biomarkers, the PD-1 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-LAG3- cells has higher predictive value.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Dec 07 [Epub ahead of print]

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

Brigham and Women's Hospital, Boston, United States., Dana-Farber Cancer Institute, Boston, MA, United States., Brigham and Women's Hospital, Boston, Massachusetts, United States., Brigham and Women's Hospital, Boston, MA, United States., Brigham and Women's Hospital., Bristol-Myers Squibb (United States), Princeton, New Jersey, United States., Yale School of Medicine, New Haven, CT, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Georgetown University Medical Center, Washington, DC, United States., Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States., Harvard Medical School, Boston, United States., The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.