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
Year: 2026
Type: article
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 (ccRCC) treated with first-line nivolumab in the phase II, nonrandomized HCRN GU16-260 trial. EXPERIMENTAL DESIGN: Pretreatment primary ccRCCs from 72 patients were analyzed via multiplex immunofluorescence and image analysis to assess nonterminally exhausted CD8+ (CD8+PD-1+TIM-3-LAG-3-) tumor-infiltrating lymphocytes (TIL), PD-1+ regulatory T cells (Treg), total and peritumoral tertiary lymphoid structures (TLS), and CD163+ tumor-associated macrophages (TAM). Clinical endpoints included objective response rate (ORR) and progression-free survival (PFS). RESULTS: The densities of CD8+PD-1+TIM-3-LAG-3- TILs, total and peritumoral TLSs, 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 TLSs; 1.10 (1.02-1.18) for peritumoral TLSs; and 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 TLSs; 0.94 (0.90-0.98) for peritumoral TLSs; and 0.77 (0.61-0.97) for TAMs]. Although the percentage of PD-1+ Tregs as a continuous variable was not associated with outcomes, at an optimal cutoff, a high percentage 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 multibiomarker models further stratified outcomes. CONCLUSIONS: Individual immune cell populations within the ccRCC microenvironment are associated with response/resistance to first-line anti-PD-1 therapy. Our findings support the development of combined immune marker models to identify patients with divergent outcomes.
Source: Clinical Cancer Research
Authors: 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
Institutions: Brigham and Women's Hospital, Harvard University, Dana-Farber Cancer Institute, Yale University, Massachusetts General Hospital, Abramson Cancer Center, University of Pennsylvania, The University of Texas Southwestern Medical Center, Emory University, Winship Cancer Institute, Columbia University Irving Medical Center, Northwestern University, Georgetown University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, Foundation for the National Institutes of Health, Bristol-Myers Squibb, Pfizer, AstraZeneca, Sanofi, Dana-Farber/Harvard Cancer Center, Exelixis, Jazz Pharmaceuticals, Innovent Biologics, Seagen, Eisai, National Institutes of Health, National Cancer Institute, U.S. National Library of Medicine, Congressionally Directed Medical Research Programs
Awards: G1328515222, Spatial genomic tools to interrogate T cell clonotypes, tumor clones and the microenvironment, G2390440901, G2541397611, G286766698, EXPANDING THE TARGETABLE TUMOR ANTIGEN REPERTOIRE OF RENAL CELL CARCINOMA, G4217112755, DF/HCC Kidney Cancer SPORE, G5822752424, DISSECTING THE RENAL CELL CARCINOMA MICROENVIRONMENT TO IDENTIFY DETERMINANTS OF OUTCOMES TO IMMUNE CHECKPOINT-BASED THERAPY, G6155655953, G6188081926, G6261537273, G7034854579, G7296843302, TERMINALLY EXHAUSTED CD8+ TUMOR-INFILTRATING LYMPHOCYTES AND M2-LIKE MACROPHAGES AS BIOMARKERS OF RESISTANCE TO FIRST-LINE ANTI-PD-1 THERAPY IN METASTATIC RCC., G8694494015, Tissue-based biomarkers of anti-PD-1-based therapy in metastatic renal cell carcinoma, Developing a Translation Pipeline for VHL Mutant Malignancies, Clinical characterization of Kidney Injury Molecule-1 (KIM-1) as a Biomarker in Renal Cell Carcinoma, Dana-Farber/Harvard Cancer Center
OpenAlex ID: W7161572300