Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
Biomarker Analysis and Treatment Dynamics Following Preoperative Ipilimumab plus Nivolumab in Locally Advanced Urothelial Cancer from the Phase IB NABUCCO Study.
СтатьяКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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Stockem Chantal F, Gil-Jimenez Alberto, Ali Hamza, van Dorp Jeroen, van Dijk Nick, van Montfoort Maurits L, Alkemade Maartje, Broeks Annegien, Seignette Iris M, Hooijberg Erik, Brugman Wim, Voogd Rhianne, van Rhijn Bas W G, Mertens Laura S, de Feijter Jeantine M, Mehra Niven, van der Heijden Antoine G, Meijer Richard P, Suelmann Britt B M, Scheper Wouter, Wessels Lodewyk F A, Vis Daniel J, van der Heijden Michiel S
Аннотация
PURPOSE: In NABUCCO, the safety and efficacy of preoperative ipilimumab plus nivolumab were assessed in stage III urothelial cancer. Encouraging responses were achieved, and ipilimumab 3 mg/kg (ipilimumab-high) seemed more effective than ipilimumab 1 mg/kg (ipilimumab-low). We explored ipilimumab plus nivolumab response biomarkers and tumor microenvironment (TME) treatment dynamics.
PATIENTS AND METHODS: Baseline formalin-fixed, paraffin-embedded tumor tissue was analyzed using PD-L1 IHC (n = 51) and whole-exome and transcriptome sequencing (both n = 53) and correlated with response. Baseline infiltration of CD8+ T cells (n = 51) and at cystectomy (n = 42) was examined. Single-cell RNA sequencing (scRNA-seq) of CD3+ T cells was conducted on on-treatment resection tissue of two responders to ipilimumab-high to explore the characteristics of CD8+ T cells within the TME.
RESULTS: High tumor mutational burden and PD-L1 positivity were associated with response to ipilimumab plus nivolumab. Nonresponding patients exhibited increased expression of a TGFβ signature. We observed increased transcription of the g2m checkpoint and e2f target in responders to ipilimumab-high and enhanced transcription of IFN-α and IFN-γ hallmarks in responders to ipilimumab-low. CD8+TCF7+ T cells accumulated in the TME of responders to ipilimumab-high. scRNA-seq of CD8A+TCF7+ T cells demonstrated enhanced expression of IL7R, CCR7, GPR15, XCL1, SELL, and LEF1.
CONCLUSIONS: Our data indicate that tumor mutational burden, PD-L1, and TGFβ are potential biomarkers for response to ipilimumab plus nivolumab in stage III urothelial cancer. An inflammatory TME might be relevant for responding to ipilimumab-low. We found that in responders to ipilimumab-high, TCF7+CD8+ T cells accumulated in the TME. scRNA-seq in two responders suggested that TCF7+CD8A+ T cells express genes associated with immunologic memory formation and T-cell homing.
PATIENTS AND METHODS: Baseline formalin-fixed, paraffin-embedded tumor tissue was analyzed using PD-L1 IHC (n = 51) and whole-exome and transcriptome sequencing (both n = 53) and correlated with response. Baseline infiltration of CD8+ T cells (n = 51) and at cystectomy (n = 42) was examined. Single-cell RNA sequencing (scRNA-seq) of CD3+ T cells was conducted on on-treatment resection tissue of two responders to ipilimumab-high to explore the characteristics of CD8+ T cells within the TME.
RESULTS: High tumor mutational burden and PD-L1 positivity were associated with response to ipilimumab plus nivolumab. Nonresponding patients exhibited increased expression of a TGFβ signature. We observed increased transcription of the g2m checkpoint and e2f target in responders to ipilimumab-high and enhanced transcription of IFN-α and IFN-γ hallmarks in responders to ipilimumab-low. CD8+TCF7+ T cells accumulated in the TME of responders to ipilimumab-high. scRNA-seq of CD8A+TCF7+ T cells demonstrated enhanced expression of IL7R, CCR7, GPR15, XCL1, SELL, and LEF1.
CONCLUSIONS: Our data indicate that tumor mutational burden, PD-L1, and TGFβ are potential biomarkers for response to ipilimumab plus nivolumab in stage III urothelial cancer. An inflammatory TME might be relevant for responding to ipilimumab-low. We found that in responders to ipilimumab-high, TCF7+CD8+ T cells accumulated in the TME. scRNA-seq in two responders suggested that TCF7+CD8A+ T cells express genes associated with immunologic memory formation and T-cell homing.