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.
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.
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.
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.
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