We investigated components of the immune tumor microenvironment as determinants of clinical outcome to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma (mccRCC) treated with frontline nivolumab in the phase 2, non-randomized HCRN GU16-260 trial.
Pre-treatment primary ccRCCs from 72 patients were analyzed by multiplex immunofluorescence and image analysis to assess non-terminally exhausted CD8+ (CD8⁺PD-1⁺TIM3⁻LAG3⁻) tumor-infiltrating lymphocytes (TILs), PD-1+ regulatory T cells (Tregs), total and peritumoral tertiary lymphoid structures (TLS), and CD163+ tumor-associated macrophages (TAMs). Clinical endpoints included objective response rate (ORR) and progression-free survival (PFS).
Densities of CD8⁺PD-1⁺TIM3⁻LAG3⁻ TILs, total and peritumoral TLS, and CD163⁺ TAMs, as continuous variables, were associated with improved ORR (Odds Ratio: 1.54 [1.10-2.16] for TILs; 1.18 [1.02-1.37] for total TLS; 1.10 [1.02-1.18] for peritumoral TLS; 2.21 [1.33-3.69] for TAMs) and longer PFS (Hazard Ratio: 0.79 [0.67-0.95] for TILs; 0.92 [0.85-0.99] for total TLS; 0.94 [0.90-0.98] for peritumoral TLS; 0.77 [0.61-0.97] for TAMs). Although % of PD-1+ Tregs as continuous variable was not associated with outcomes, at an optimal cut-off, high % of PD-1+ Tregs tended to be associated with lower ORR (12.5% vs 43.6%, p=0.093) and was associated with shorter PFS (3.4 vs 10.9 months, p<0.001). The biomarkers were not strongly correlated with each other and their integration in multi-biomarker models further stratified outcomes.
Individual immune cell populations within the ccRCC microenvironment are associated with response/resistance to frontline anti-PD-1 therapy. Our findings support the development of combined immune marker models to identify patients with divergent outcomes.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2026 May 18 [Epub ahead of print]
Nourhan El Ahmar, Morgan A Paul, Berkay Simsek, Sayed Matar, Opeyemi A Jegede, Yasmin Nabil Laimon, Varunika Savla, Razan Mohanna, Gabriel Roberti de Oliveira, Aseman Bagheri Sheshdeh, Thomas Denize, Destiny J West, Maxwell D Seager, Maxine Sun, Toni K Choueiri, Wanling Xie, Gordon J Freeman, Arlene H Sharpe, David A Braun, Naomi B Haas, Hans Hammers, Mehmet A Bilen, Mark Stein, Jeffrey A Sosman, Catherine J Wu, David F McDermott, Michael B Atkins, Sabina Signoretti
Brigham and Women's Hospital Boston United States., Dana-Farber Cancer Institute Boston, MA United States., Yale New Haven Hospital New Haven, CT United States., Brigham and Women's Hospital Boston, MA United States., Massachusetts General Hospital Boston United States., Harvard University Boston United States., Yale University New Haven, CT United States., University of Pennsylvania Philadelphia, PA United States., The University of Texas Southwestern Medical Center Dallas, TX United States., Emory University Hospital Atlanta, GA United States., Columbia University New York, NY United States., Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL United States., Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA United States., Georgetown University Medical Center Washington, DC United States.