Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear Cell Renal Cell Carcinoma: analyses of the HCRN GU16-260 trial

PURPOSE: 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. EXPERIMENTAL DESIGN: 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). RESULTS: 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. CONCLUSION: 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.

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Journal
Clinical Cancer Research
Published
2026-05-18
DOI
https://doi.org/10.1158/1078-0432.ccr-26-0216
Primary Topic
Renal cell carcinoma treatment
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article
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article

Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear Cell Renal Cell Carcinoma: analyses of the HCRN GU16-260 trial

Gabriel Roberti de Oliveira, Thomas Denize, Mark Stein, Opeyemi A. Jegede et al.
Clinical Cancer Research
Renal cell carcinoma treatment
article

Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear Cell Renal Cell Carcinoma: analyses of the HCRN GU16-260 trial

Gabriel Roberti de Oliveira, Thomas Denize, Mark Stein, Opeyemi A. Jegede, Varunika Savla, Maxwell D. Seager, Morgan A. Paul, Hans J. Hammers, Aseman Bagheri Sheshdeh, Berkay Simsek, Naomi B. Haas, Mehmet A. Bilen, Michael B. Atkins, Sabina Signoretti, David F. McDermott, Razan Mohanna, Catherine J. Wu, Destiny J. West, David A. Braun, Nourhan El Ahmar, Jeffrey A. Sosman, Sayed Matar, Gordon J. Freeman, Wanling Xie, Arlene H. Sharpe, Yasmin Nabil. Laimon, Toni K. Choueiri, Maxine Sun
article en

Abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: 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). RESULTS: 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. CONCLUSION: 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
Brigham and Women's Hospital (US), Beth Israel Deaconess Medical Center (US), Yale New Haven Hospital (US), Harvard University (US), Georgetown University (US), Georgetown University Medical Center (US), Emory University Hospital (US), Harvard University Press (US), Yale University (US), Massachusetts General Hospital (US), Dana-Farber Cancer Institute (US), Dana-Farber/Harvard Cancer Center (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Columbia University (US), University of Pennsylvania (US), The University of Texas Southwestern Medical Center (US), Philadelphia University (US)
Good health and well-being
Openalex Percentile: Top 8%
Renal cell carcinoma treatment
DOISourceOpenAlex
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