Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
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.
СтатьяКлиническое исследование II фазыНазвание и аннотация: Перевод в очереди
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El Ahmar Nourhan, Paul Morgan A, Simsek Berkay, Matar Sayed, Jegede Opeyemi A, Laimon Yasmin Nabil, Savla Varunika, Mohanna Razan, de Oliveira Gabriel Roberti, Bagheri Sheshdeh Aseman, Denize Thomas, West Destiny J, Seager Maxwell D, Sun Maxine, Choueiri Toni K, Xie Wanling, Freeman Gordon J, Sharpe Arlene H, Braun David A, Haas Naomi B, Hammers Hans, Bilen Mehmet A, Stein Mark, Sosman Jeffrey A, Wu Catherine J, McDermott David F, Atkins Michael B, Signoretti Sabina
Аннотация
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.
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.
Предметные рубрики MeSH
HumansCarcinoma, Renal CellTumor MicroenvironmentKidney NeoplasmsFemaleLymphocytes, Tumor-InfiltratingBiomarkers, TumorMaleProgrammed Cell Death 1 ReceptorTumor-Associated MacrophagesNivolumabImmune Checkpoint InhibitorsMiddle AgedAgedT-Lymphocytes, RegulatoryAntigens, CDAdultT-Cell ExhaustionTreatment OutcomePrognosis